thiohydantoins and Prostatic-Neoplasms--Castration-Resistant

The treatment of castration-sensitive prostate cancer (CSPC) has been revolutionized by the advent of apalutamide and enzalutamide in this setting; however, a direct comparison between these agents is still missing. In the current paper, we performed both Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses aimed to compare clinical outcomes in CSPC patients treated with apalutamide or enzalutamide; data from 3323 CSPC patients enrolled in the ARCHES, ENZAMET and TITAN phase III studies were included. According to our results, apalutamide showed better results in terms of overall survival (OS) and safety in patients with CSPC, while better outcomes were observed with enzalutamide in the low-volume subgroup.

Topics: Castration; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

To date, the efficacy of the androgen receptor inhibitors enzalutamide and apalutamide for the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC) has not been compared directly in a clinical trial setting. Indirect comparisons can be used to assess relative efficacy and provide important information to guide treatment decisions. PROSPER and SPARTAN were double-blind, randomized, placebo-controlled, phase III trials in patients with nmCRPC with overall similar study designs and inclusion and exclusion criteria. Using an anchored matching-adjusted indirect comparison, based on the final data from the PROSPER and SPARTAN studies, we assessed the comparative efficacy of enzalutamide and apalutamide, both plus androgen deprivation therapy.. Using placebo as the common comparator, individual patient data from PROSPER were matched to the aggregate patient data from SPARTAN and efficacy endpoints from PROSPER were re-weighted accordingly. Patient baseline characteristics and endpoints were clinically and statistically tested to identify potential effect modifiers, according to National Institute for Health and Care Excellence guidelines. Hazard ratios for overall survival (OS), metastasis-free survival (MFS), and time to chemotherapy (TTCx) were re-estimated for PROSPER using weighted Cox proportional hazards models and indirectly compared with those of SPARTAN using a Bayesian network meta-analysis.. Estimated hazard ratios [95% credible interval (CrI)] for enzalutamide versus apalutamide were 0.80 (95% CrI 0.58-1.10) for OS, 0.94 (95% CrI 0.69-1.29) for MFS2, and 0.90 (95% CrI 0.63-1.29) for TTCx. Similar results were seen for sensitivity analyses conducted for OS and MFS. Bayesian probability analyses showed a 91.7% favoring enzalutamide for OS, 65.1% for MFS, and 71.4% for TTCx.. The results of this matching-adjusted indirect comparison of final data from PROSPER and SPARTAN indicate comparable efficacy of enzalutamide and apalutamide with potentially a greater probability of longer MFS, OS, and TTCx in patients with nmCRPC treated with enzalutamide versus apalutamide.

Topics: Androgen Antagonists; Bayes Theorem; Benzamides; Clinical Trials, Phase III as Topic; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Thiohydantoins; Treatment Outcome

The most recent overall survival (OS) and adverse event (AE) data have not been compared for the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treatment alternatives.. We performed a systematic review and network meta-analysis focusing on OS and AE according to the most recent apalutamide, enzalutamide, and darolutamide reports. We systematically examined and compared apalutamide vs. enzalutamide vs. darolutamide efficacy and toxicity, relative to ADT according to PRISMA. We relied on PubMed search for most recent reports addressing prospective randomized trials with proven predefined OS benefit, relative to ADT: SPARTAN, PROSPER, and ARAMIS. OS represented the primary outcome and AEs represented secondary outcomes.. Overall, data originated from 4117 observations made within the three trials that were analyzed. Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order. In the subgroup of PSA-doubling time (PSA-DT) ≤ 6 months patients, enzalutamide ranked first, followed by darolutamide and apalutamide in that order. Conversely, in the subgroup of PSA-DT 6-10 months patients, darolutamide ranked first, followed by apalutamide and enzalutamide, in that order. Regarding grade 3+ AEs, darolutamide was most favorable, followed by enzalutamide and apalutamide, in that order.. The current network meta-analysis suggests the highest OS efficacy and lowest grade 3+ toxicity for darolutamide. However, in the PSA-DT ≤ 6 months subgroup, the highest efficacy was recorded for enzalutamide. It is noteworthy that study design, study population, and follow-up duration represent some of the potentially critical differences that distinguish between the three studies and remained statistically unaccounted for using the network meta-analysis methodology. Those differences should be strongly considered in the interpretation of the current and any network meta-analyses.

Topics: Benzamides; Humans; Male; Network Meta-Analysis; Nitriles; Phenylthiohydantoin; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins; Treatment Outcome

Several novel androgen receptor (AR)-inhibitors have been introduced for nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the improvement of survival outcomes which need to be balanced against the risk of adverse events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating enzalutamide, apalutamide and darolutamide in nmCRPC patients, to assess overall survival (OS), incidence and risk of adverse drug events, adverse-events-related death and adverse-events-related treatment discontinuation. We selected three RCTs (SPARTAN, PROSPER and ARAMIS). New hormonal agents administration resulted in better OS, despite the increased risk of several any grade and grade 3-4 adverse events. In the decision-making process, careful evaluation of expected adverse events, patients' comorbidities and maintenance of quality of life are mandatory.

Topics: Androgen Receptor Antagonists; Benzamides; Comorbidity; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Quality of Life; Randomized Controlled Trials as Topic; Thiohydantoins

Prostate cancer is considered the second most diagnosed cancer, and one of the most common causes of death from cancer in men. Apalutamide is an effective, safe, and well-tolerated agent used for the treatment of men with non-metastatic Castration-Resistant Prostate Cancer (nmCRPC) and metastatic Hormone-Naive Prostate Cancer (mHNPC). Androgen receptor signaling is a leading factor that drives these prostate tumors. USFDA has approved apalutamide on 14 February 2018 as an agent that targets androgen receptor signaling through inhibition causing significant improvement in metastasis-free survival in patients with prostate cancer.. In this review, various aspects related to apalutamide have been summarized which involve the mechanism of action, chemistry, synthesis, pharmacokinetics, pharmacodynamics, adverse reactions, and safety parameters.. The literature was thoroughly searched in the relevant databases to identify studies published in this field during recent years. Special attention has been given to apalutamide clinical trials phases and its promising future as one of the first-line agents for the treatment of patients with advanced prostate cancer.. Ongoing trials are progressing for apalutamide monotherapy and also for its combinations in other disease settings. The expected results of such trials will shape the future scenario of prostate cancer therapy.. This review article has highlighted different aspects of Apalutamide like its mechanism of action, adverse effects, pharmacokinetics, pharmacodynamics, clinical trials among others. The contents of this article should make an excellent read for prospective researchers in this field.

Topics: Androgen Receptor Antagonists; Humans; Male; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins

Though prostate cancer usually responds to androgen deprivation therapy (ADT) in the beginning, the majority of prostate cancers will develop castration resistance over time. The androgen receptor (AR) pathway is often found to be activated in castration resistant prostate cancer (CRPC). Thus, AR signalling remains a therapeutic target upon the development of CRPC. The term M0CRPC is used when ADT leads to castration resistance and there are no metastases detectable by means of conventional imaging. Until recently, there was no therapeutic standard for this group of patients. With the PROSPER-, SPARTAN- and ARAMIS-studies three large placebo-controlled phase III trials have been published lately that showed a significant benefit in metastasis-free survival in men with M0CRPC and short PSA doubling time (PSADT). The efficacy data are very similar in these studies, meaning that the drugs' safety profiles, final analyses of overall survival and their availability will be more important to help clinicians decide which of these three drugs they use for their patients with M0CRPC.

Topics: Androstenes; Benzamides; Clinical Trials as Topic; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins

Topics: Androgen Receptor Antagonists; Animals; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins

Metastatic prostate cancer is associated with considerable morbidity and mortality. Standard treatment for non-metastatic prostate cancer, to prevent metastatic progression, is androgen deprivation therapy (ADT); however, many patients will eventually develop castration-resistant prostate cancer (CRPC), which can prove challenging to treat. Between the stages of non-metastatic androgen-sensitive disease and metastatic CRPC is an intermediate disease state that has been termed non-metastatic CRPC (nmCRPC), which is a heterogeneous, man-made disease stage that occurs after a patient who has no radiological evidence of metastasis shows evidence of cancer progression even after ADT. Awareness of nmCRPC has risen owing to an increased use of ADT and its eventual failure. Men with nmCRPC are at a high risk of progression to mCRPC, with historically few options to halt this process. However, in the past two decades, multiple therapies have been investigated for the treatment of nmCRPC, including endothelin receptor antagonists and bone-targeted therapies, but none has changed the standard of care. In the past decade, the efficacy of androgen receptor pathway-targeting modalities has been investigated. Three novel nonsteroidal antiandrogen agents for treating high-risk nmCRPC have been investigated; the PROSPER, SPARTAN and ARAMIS trials were phase III, randomized, placebo-controlled clinical trials that investigated the efficacy and safety of enzalutamide, apalutamide and darolutamide, respectively. All three therapeutics showed statistically significant improvements in metastasis-free survival, progression to antineoplastic therapy was lengthened and at final analysis, overall survival was significantly improved. The comparative efficacy and safety of all three agents has not yet been investigated in a comprehensive clinical trial, but approval of these medications by the FDA and other regulatory agencies means that providers now have three effective therapeutic options to augment ADT for patients with nmCRPC.

Topics: Adenocarcinoma; Benzamides; Humans; Male; Neoplasm Staging; Nitriles; Nonsteroidal Anti-Androgens; Phenylthiohydantoin; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic; Survival Rate; Thiohydantoins

Novel hormonal therapies have been recently investigated in non-metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the efficacy and safety of novel hormonal therapies in non-metastatic CRPC.. The primary outcome was metastasis-free survival (MFS). The secondary endpoints were overall survival (OS), time to PSA progression and safety. We planned a subgroup analysis according to the PSA doubling time (> 6 vs < 6 months), Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0) and concomitant use of bone-targeting agent (yes vs no).. Pooled analysis of novel hormonal therapies revealed significantly increased MFS compared with placebo (hazard ratio (HR): HR = 0.32, 95% CI 0.25-0.41; p < 0.00001). The subgroup analysis showed a statistically significant MFS advantage in favour of men with the lower ECOG performance status. Other secondary endpoints favoured the novel hormonal therapies. The relative risk (RR) of grade ≥ 3 adverse events and ≥ 3 hypertension was 1.31 and 1.39, respectively.. This study confirmed the efficacy and safety of the novel hormonal therapies in non-metastatic CRPC.

Topics: Antineoplastic Agents, Hormonal; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic; Survival Rate; Thiohydantoins

Apalutamide and enzalutamide are next-generation androgen receptor inhibitors that demonstrated efficacy in placebo-controlled studies (SPARTAN for apalutamide; PROSPER for enzalutamide) when used in combination with androgen deprivation therapy (ADT) for treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). In the absence of comparative studies between these agents, the present study sought to indirectly compare metastasis-free survival (MFS) and overall survival (OS) in patients with nmCRPC who received these therapies.. Individual patient-level data from SPARTAN (apalutamide plus ADT) and published data from PROSPER (enzalutamide plus ADT) were utilized. An anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting the patients from the SPARTAN study to match baseline characteristics reported for PROSPER. Hazard ratios (HRs) for MFS and OS were re-estimated for SPARTAN using weighted Cox proportional hazards models and indirectly compared with those of PROSPER using a Bayesian network meta-analysis.. From the SPARTAN population (N = 1207), a total of 1171 patients were matched to the PROSPER population (N = 1401). The recalculated HRs (95% confidence interval) for apalutamide versus ADT based on the reweighted SPARTAN data to mimic the PROSPER patient population were 0.26 (0.21; 0.33) for MFS and 0.62 (0.41; 0.94) for OS. MAIC-based HRs (95% credible interval) for apalutamide versus enzalutamide were 0.91 (0.68; 1.22) for MFS and 0.77 (0.46; 1.30) for OS. The Bayesian probabilities of apalutamide being more effective than enzalutamide were 73.6% for MFS and 83.5% for OS.. MAIC results suggest that nmCRPC patients treated with apalutamide have a higher probability of a more favorable MFS and OS compared with those treated with enzalutamide.

Topics: Androgen Receptor Antagonists; Bayes Theorem; Benzamides; Disease-Free Survival; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Proportional Hazards Models; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Novel combination therapies are currently the standard systemic treatment for metastatic hormone-sensitive prostate cancer. As a result, the overall survival of patients can be extended by approximately 1.5 years. The taxane docetaxel, the CYP17 inhibitor abiraterone and the second generation antiandrogen apalutamide can currently be used as a combination partner for classic androgen deprivation. While the de novo synthesis of testosterone is the rationale for abiraterone or apalutamide combination, taxanes offer a promising approach in the presence of primarily androgen-independent prostate cancer cells. Due to the increased rate of side effects caused by combination therapy, it is important to clarify in daily clinical practice which patient group benefits in particular from the respective combination therapy. Hereby, the metastatic pattern, general condition and age play an important role. While there is good evidence of the use of docetaxel or abiraterone in visceral metastasis, apalutamide offers a very wide range of uses. Ultimately, the recommendation for combination therapy is always an individual decision that needs to be discussed with the patient, considering the benefits and risks.

Topics: Androgen Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Therapy, Combination; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

The FDA has approved three androgen receptor inhibitors-enzalutamide, apalutamide, and darolutamide-for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

Topics: Androgen Receptor Antagonists; Benzamides; Drug Approval; History, 21st Century; Humans; Male; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Randomized Controlled Trials as Topic; Thiohydantoins

Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). This is an inspiring drug discovery story created by an amazing interdisciplinary collaboration. Equally important, the successful clinical use of enzalutamide proves the notion that the second-generation AR antagonists can serve as hormonal therapeutics for three forms of advanced prostate cancer. This has been further verified by the recent FDA approval of the other two second-generation AR antagonists, apalutamide and darolutamide, for the treatment of prostate cancer. This review focuses on the rational design and discovery of these three second-generation AR antagonists, and then highlights their syntheses, clinical studies, and use. Strategies to overcome the resistance to the second-generation AR antagonists are also reviewed.

Topics: Androgen Receptor Antagonists; Benzamides; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Receptors, Androgen; Signal Transduction; Thiohydantoins

Novel androgen signaling inhibitors are currently standard of care in the treatment of patients with prostate cancer. Second-generation androgen receptor antagonists have demonstrated efficacy in earlier disease settings, fulfilling an unmet need in the treatment of patients with advanced prostate cancer.. The present article focuses on the development and establishment of apalutamide among the available treatment options for prostate cancer. A literature search was performed in Pubmed/Medline for past studies and reviews of the drug. Ongoing clinical trials were also examined in the Clinicaltrials.gov online database.. Apalutamide has demonstrated benefit for patients with non-metastatic castration resistant and metastatic hormone naive prostate cancer. It is an efficacious, tolerable, and convenient oral agent, thus a valuable addition in the armamentarium of prostate cancer therapeutics for both non-metastatic castrate resistant and metastatic hormone naïve prostate cancer. Ongoing trials are investigating the drug as monotherapy and in combinations in other disease settings. Results are expected to further expand the drug's indications and shape the future landscape of prostate cancer therapy.

Topics: Androgen Receptor Antagonists; Animals; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome; Xenograft Model Antitumor Assays

Studies using apalutamide, enzalutamide, or darolutamide have shown improved metastasis free survival (MFS) rates, leaving clinicians with a dilemma of choosing one over the other, for nonmetastatic castration recurrent prostate cancer (nmCRPC). We performed a network meta-analysis to provide an indirect comparison of oncologic outcomes and adverse events (AEs) of these medications.. We searched PubMed, MEDLINE, and SCOPUS databases, for studies reporting apalutamide, enzalutamide, or darolutamide until January 25, 2020. Results were input into an EndNote library, and data were extracted into a predefined template. Progression free survival (PFS) was defined as radiologic progression or death. Network meta-analysis was done using R and meta-analysis was performed with RevMan v. 5. Surface under the cumulative ranking (SUCRA) value was used to provide rank probabilities.. We found 3 studies reporting results for apalutamide, enzalutamide, and darolutamide. MFS was significantly lower in patients receiving darolutamide compared to both apalutamide (hazard ratio [HR]: 0.73, 95% confidence interval [CI]: 0.55-0.97) and enzalutamide (HR: 0.71, 95% CI: 0.54-0.93). MFS was similar for enzalutamide and apalutamide (HR: 0.97, 95% CI: 0.73-1.28). In PFS, apalutamide showed a slightly higher rate compared to darolutamide (HR: 0.76, 95% CI: 0.59-0.99). There was no difference in overall survival (OS) between any of the medications. There was no statistically significant difference in AEs profile of the 3 medications. However, darolutamide had the highest SUCRA value and probability of being the most preferred medication based on AEs profile.. Enzalutamide and apalutamide had similar and higher MFS rate in indirect comparison with darolutamide. In cases where AEs are concerning, darolutamide might be the preferred agent.

Topics: Benzamides; Humans; Male; Network Meta-Analysis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins; Treatment Outcome

Non-metastatic castration resistant prostate cancer (nmCRPC) is defined as a disease state withlack of radiographic evidence of metastatic disease, a confirmed rising PSA level on continuous ADT and maintaining a castrate level of testosterone following definitive therapy. Prior to the publication of PROSPER, SPARTAN and ARAMIS, no trials have demonstrated a clinical benefit for these patients. Recently enzalutamide, apalutamide, and darolutamide respectively, were tested in this disease setting with metastasis free survival (MFS) as the primary endpoint for each trial. In this review article, we define key terms related to the discussion of nmCRPC, examine the clinical trial design, and safety profile for each of these three key clinical trials and present updated overall survival (OS) results from these studies. Also we specifically discuss the key clinical trial results including the primary endpoint of MFS for each trial as well as quality of life effects of these three androgen receptor antagonists. Finally, this article examines the potential impact of molecular imaging testing on the applicability of these clinical trial results.

Topics: Androgen Receptor Antagonists; Antigens, Surface; Benzamides; Biomarkers, Tumor; Disease-Free Survival; Glutamate Carboxypeptidase II; Humans; Male; Molecular Imaging; Nitriles; Phenylthiohydantoin; Placebos; Positron-Emission Tomography; Prostate; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Quality of Life; Randomized Controlled Trials as Topic; Thiohydantoins

Prostate cancer is the fifth leading cause of cancer-related death among men with the majority of deaths linked to metastatic disease. Accumulating clinical data have confirmed the substantial survival benefit of the addition of docetaxel or androgen signaling inhibitors to androgen deprivation therapy for the treatment of metastatic castration-sensitive prostate cancer (mCSPC). Apalutamide, a next-generation androgen receptor inhibitor, has recently been shown to provide an added survival benefit in the treatment of mCSPC and consequently approved for this indication. This review summarizes the body of evidence with regards to the preclinical activity and clinical efficacy of apalutamide with a specific focus on its efficacy in the treatment of mCSPC.

Topics: Androgen Receptor Antagonists; Androgens; Clinical Trials as Topic; Humans; Male; Neoplasm Metastasis; Patient Reported Outcome Measures; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins

Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77-0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78-0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69-0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74-0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Benzamides; Humans; Kallikreins; Male; Network Meta-Analysis; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins; Treatment Outcome

Apalutamide (Erleada

Topics: Administration, Oral; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Disease-Free Survival; Humans; Male; Multicenter Studies as Topic; Progression-Free Survival; Prostate; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins

Apalutamide (marketed as Erleada

Topics: Androgen Antagonists; Animals; Humans; Male; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Receptors, Androgen; Thiohydantoins

High-risk nonmetastatic castration-resistant prostate cancer is a lethal disease that previously lacked clear treatment options. Progression to bone metastases is associated with significant morbidity and high cost. Apalutamide, an androgen receptor inhibitor, has substantial clinical response in nonmetastatic castration-resistant prostate cancer. Apalutamide + androgen deprivation therapy is well tolerated and improves metastasis-free survival, progression-free survival and time to symptomatic progression, and is associated with a favorable trend of improved overall survival. Future research is needed to elucidate mechanisms of resistance to treatment with androgen signaling inhibitors.

Topics: Androgen Antagonists; Clinical Trials, Phase III as Topic; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Patient Reported Outcome Measures; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Signal Transduction; Thiohydantoins; Treatment Outcome

 Prostate cancer is the most common cancer in men. Regardless of the initial treatment of localized disease, almost all patients develop castration resistant prostate cancer (CRPC). A better understanding of the molecular mechanisms behind castration resistance has led to the approval of novel oral androgen receptor (AR) antagonists, such as enzalutamide and apalutamide. Indeed, research has accelerated with numerous agents being studied for the management of CRPC. Areas covered: Herein, the authors present currently used and emerging AR antagonists for the treatment of CRPC. Emerging agents include darolutamide, EZN-4176, AZD-3514, and AZD-5312, apatorsen, galeterone, ODM-2014, TRC-253, BMS-641988, and proxalutamide. Expert opinion: Further understanding of the mechanisms leading to castration resistance in prostate cancer can reveal potential targets for the development of novel AR antagonists. Current novel agents are associated with modest clinical and survival benefit, while acquired resistance and safety issues are under continuous evaluation. The combination of AR antagonists used and ideal sequencing strategies are key tasks ahead, along with the investigation of molecular biomarkers for future personalized targeted therapies. In the future, the challenge will be to determine an AR antagonist with the best combination of outcome and tolerability.

Topics: Androgen Receptor Antagonists; Animals; Benzamides; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins

Nonmetastatic castration-resistant prostate cancer (nmCRPC) comprises a relatively narrow niche of advanced prostate cancer, but the treatment landscape for men with nmCRPC has drastically changed over the past year. Prior to the SPARTAN and PROSPER trials, men with nmCRPC were commonly treated with first-generation androgen receptor antagonists, such as bicalutamide or flutamide, or with estrogens or ketoconazole, none of which were associated with any proven survival benefit. The SPARTAN trial evaluated apalutamide versus placebo for men with nmCRPC and found that apalutamide significantly improved metastasis-free survival (MFS), the primary endpoint of this trial. Similarly, the PROSPER trial showed that enzalutamide significantly improved MFS compared with placebo for men with nmCRPC. In both trials, the data for overall survival was immature at the time of analysis. The SPARTAN and PROSPER trials led to the approval of apalutamide and enzalutamide, respectively, for men with nmCRPC. More recently, the phase 3 trial ARAMIS showed that darolutamide, a novel androgen receptor antagonist, also improves MFS compared with placebo for men with nmCRPC, and this trial is expected to garner regulatory approval for darolutamide in the nmCRPC setting. Novel imaging modalities are becoming more prevalent for the diagnostic evaluation of men with prostate cancer and are more sensitive than conventional bone or CT scans for detection of oligometastatic disease that previously was undetected. These modalities are likely to reduce the incidence and prevalence of nmCRPC in the near future. Ultimately, the treatment options for men with nmCRPC have significantly improved over the past 2 years.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Agents; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins; Treatment Outcome

The basic therapy of metastatic prostate carcinoma is androgen deprivation therapy. Unfortunately, almost all patients develop resistance to treatment that leads to castration-resistant prostate cancer. From 2010, 6 new active substances were registered for the treatment of metastatic castration-resistant prostate cancer, which dramatically improved the overall survival of patients. Two of these are treatments for the androgenic axis, the other drugs or therapeutic methods are immunotherapy, chemotherapy, isotope treatment and RANK-ligand inhibition. The year 2018 was a major success in the treatment of nonmetastatic castration-resistant prostate carcinoma, with the FDA authorizing both apalutamide and enzalutamide at this stage. The aim of this review is to present the standard of care of metastatic castration-resistant prostate cancer by disease stage, and to introduce the emerging treatment modalities presently assessed in clinical trials and discuss the open questions.. A metasztatikus prosztatakarcinóma bázisterápiája az androgéndeprivációs terápia. Sajnos szinte minden betegnél rezisztencia alakul ki a kezelésre, mely kasztrációrezisztens prosztatarákhoz vezet. A metasztatikus kasztrációrezisztens prosztatarák kezelésében 2010-tõl 6 új hatóanyag került törzskönyvezésre, melyek drámaian javították a betegek teljes túlélését. Ezek közül kettõ az androgéntengelyt célzó kezelések közé tartozik, a többi hatóanyag, illetve terápiás eljárás: immunterápia, kemoterápia, izotópkezelés és RANK-ligandum-gátlás. A nem metasztatikus kasztrációrezisztens prosztatakarcinóma kezelésében a 2018-as év átütõ sikert hozott, az FDA engedélyezte mind az apalutamid, mind az enzalutamid használatát ebben a stádiumban. Közleményünk célja kasztrációrezisztens elõrehaladott prosztatadaganatban stádiumok szerint a már egyértelmû evidenciák ismertetése, az új fejlesztések bemutatása, nyitott kérdések megvitatása.

Topics: Benzamides; Humans; Male; Neoplasm Metastasis; Neoplasm Staging; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Urologists have been using oral nonsteroidal antiandrogens (AA) for 30 years as a component of combined androgen blockade. In February 2018, a new third generation AA, apalutamide, became available for the first time for non-metastatic (M0) castrate resistant prostate cancer (CRPC). Apalutamide was found to delay the presence of metastases (metastases free survival-MFS) by approximately 2 years versus placebo in M0 CRPC. While overall survival benefit has yet to be established, the MFS benefit is clinically meaningful and urology practices should be equipped to manage patients using this new oral agent. Since the majority of patients remain under urologic care when this disease stage develops and because the drug is straightforward to administer, urology practices are ideal to identify and treat. The objective of this brief article is to discuss the typical patient profile for use of apalutamide and to review the pros and cons of use and common side effects and management.

Topics: Disease-Free Survival; Humans; Male; Neoplasm Staging; Practice Guidelines as Topic; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

Apalutamide is a competitive inhibitor of the androgen receptor and binds directly to the ligand-binding domain. The US Food and Drug Administration approved apalutamide on 14 February 2018 for use in patients with nonmetastatic castration-resistant prostate cancer based upon results from the phase III SPARTAN trial demonstrating significantly longer metastasis-free survival over placebo. The SPARTAN trial evaluated 1207 patients with nonmetastatic castration-resistant prostate cancer who were randomized 2:1 to apalutamide or placebo in combination with androgen deprivation therapy. Patients who received apalutamide experienced statistically significantly longer metastasis-free survival (40.5 versus 16.2 months, hazard ratio 0.28 (95% confidence interval = 0.23-0.35); P < 0.0001), which was the major efficacy outcome. Rash, hypothyroidism, and fracture were reported to occur more frequently with apalutamide than placebo. Based upon these results, apalutamide was deemed a safe and effective treatment option for patients with nonmetastatic castration-resistant prostate cancer. Clinical trials are ongoing to expand its indication in the metastatic setting, and identify additional roles for apalutamide in the management of prostate cancer such as in the castrate-sensitive metastatic setting.

Topics: Androgen Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Receptors, Androgen; Thiohydantoins; Treatment Outcome

Prostate cancer (PCa) is the most common cancer in elderly males. Androgen deprivation therapy (ADT) is still the cornerstone of initial treatment; however, the vast majority of patients develop castration-resistant prostate cancer (CRPC). Several studies with numerous androgen receptor (AR)-directed agents have emerged since the approval of abiraterone acetate and enzalutamide. One of these agents is apalutamide, which seems to be a promising AR antagonist for the treatment of CRPC. Areas covered: The authors review Phase I, II, and III studies for apalutamide, in a large spectrum of PCa (from low-risk to metastatic CRPC [mCRPC]) patients as sole treatment or in the setting of combined therapy. Expert opinion: Apalutamide is an oral, investigational, AR antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. It has shown favorable safety profile and therapeutic index in Phase I studies, good tolerance and efficacy in patients with high-risk CRPC in Phase II studies. Also, results were promising in a recent phase III study in patients with non-mCRPC who were at high risk for the development of metastasis. These data may offer potential advantages over the second-generation antiandrogens.

Topics: Aged; Androgen Receptor Antagonists; Animals; Disease Progression; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Topics: Antineoplastic Agents; Benzamides; Humans; Male; Neoplasm Staging; Nitriles; Nonsteroidal Anti-Androgens; Outcome Assessment, Health Care; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Survival Analysis; Thiohydantoins

Five new agents have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer, including two targeting androgen receptor signaling (abiraterone acetate plus prednisone; enzalutamide). Recognition that these tumors remain driven by androgen receptor signaling has prompted clinical evaluation of these agents at earlier states in the prostate cancer disease continuum, along with the continued development of new agents targeting this pathway. Areas covered: This article focuses on apalutamide, a next-generation nonsteroidal antiandrogen, with current literature queried in PubMed/Medline. A narrative review strategy describes studies from engineering of the compound through to a 5-year outlook. Expert commentary: In the phase III SPARTAN study, apalutamide significantly improved metastasis-free survival in patients with nonmetastatic castration-resistant prostate cancer - the first treatment approved by the US Food and Drug Administration for this indication. Phase III studies are under way to determine the clinical benefit of apalutamide in other disease states. Given the multiplicity of prostate cancer treatment options now available, there is a need to maximize individual patient benefit through the development and validation of predictive biomarkers of sensitivity to drugs that can be used in real time to determine the optimal sequence and combinations of treatments for patients in need.

Topics: Androgen Receptor Antagonists; Animals; Biomarkers, Tumor; Drug Development; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Survival Rate; Thiohydantoins

Patients with recurrent, nonmetastatic prostate cancer after curative intent therapy can experience a heterogeneous clinical course ranging from indolent disease that can be observed for years to a rapidly progressive disease that is metastatic in a relatively short time. Patients with short prostate-specific antigen (PSA) doubling times are at risk for early development of metastatic disease and are frequently placed on androgen deprivation therapy. Although castration-resistant disease inevitably occurs in these patients, most therapies for castration-resistant disease have shown benefit in the metastatic setting. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor, preventing androgen receptor translocation, DNA binding and androgen receptor-mediated transcription. Apalutamide showed improved metastasis-free survival and prolonged time to symptomatic progression in men with nonmetastatic castration-resistant prostate cancer with a short PSA doubling time.

Topics: Androgen Antagonists; Humans; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

A mechanism allowing castration resistant prostate cancer cells to escape the effects of conventional anti-hormonal treatments is the synthesis of constitutively active, C-terminally truncated androgen receptor (AR)-variants. Lacking the entire or vast parts of the ligand binding domain, the intended target of traditional endocrine therapies, these AR-variants (termed ARΔLBD) are insensitive to all traditional treatments including second generation compounds like abiraterone, enzalutamide or ARN-509. Although ARΔLBD are predominantly products of alternative splicing, they can also be products of nonsense mutations or proteolytic cleavage. In this review, we will discuss the etiology and function of c-terminally truncated AR-variants and their clinical significance as markers/targets for the treatment of castration resistant prostate cancer.

Topics: Alternative Splicing; Androgens; Androstenes; Androstenols; Animals; Benzamides; Biomarkers, Tumor; Codon, Terminator; Disease Progression; Epithelial-Mesenchymal Transition; Genetic Variation; Genome, Human; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Domains; Signal Transduction; Thiohydantoins; Transcription Factors

The approval of abiraterone and enzalutamide for the treatment of advanced castration-resistant prostate cancer heralded a paradigm shift in the management of this disease. Nevertheless, new and improved treatments are needed since the disease remains incurable for the majority of these patients. In this article, we review the biology of castration-resistant disease as well as emerging therapeutic compounds directed at the androgen receptor, including galeterone, VT-464, ARN-509, and ODM-201. Mechanisms of action, early clinical data, and ongoing clinical studies for these compounds are all reviewed. The need to find optimal sequencing and combination strategies as well as the need for predictive biomarkers of response to these agents is discussed.

Topics: Androgen Receptor Antagonists; Androstadienes; Androstenes; Benzamides; Benzimidazoles; Humans; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Receptors, Androgen; Thiohydantoins; Triazoles

Various molecular mechanisms play a role in the development of resistance to androgen deprivation therapy in castration-resistant prostate cancer (CRPC).. To understand the mechanisms and biological pathways associated with the progression of prostate cancer (PCa) under systemic androgen depletion or administration of the novel antiandrogens abiraterone, enzalutamide, and ARN-509. This review also examines the introduction of novel combinational approaches for patients with CRPC.. PubMed was the data source. Keywords for the search were castrate resistant prostate cancer, abiraterone, enzalutamide resistance mechanisms, resistance to androgen deprivation, AR mutations, amplifications, splice variants, and AR alterations. Papers published before 1990 were excluded from the review, and only English-language papers were included.. This review summarizes the current literature regarding the mechanisms implicated in the development of CRPC and the acquisition of resistance to novel antiandrogen axis agents. The review focuses on androgen biosynthesis in the tumor microenvironment, androgen receptor (AR) alterations and post-transcriptional modifications, the role of glucocorticoid receptor, and alternative oncogenic signaling that is derepressed on maximum AR inhibition and thus promotes cancer survival and progression.. The mechanisms implicated in the development of resistance to AR inhibition in PCa are multiple and complex, involving virtually all classes of genomic alteration and leading to a host of selective/adaptive responses. Combinational therapeutic approaches targeting both AR signaling and alternative oncogenic pathways may be reasonable for patients with CRPC.. We looked for mechanisms related to the progression of PCa in patients undergoing hormonal therapy and treatment with novel drugs targeting the AR. Based on recent data, combining maximal AR inhibition with novel agents targeting other tumor-compensatory, non-AR-related pathways may improve the survival and quality of life of patients with castration-resistant PCa.

Topics: Androgen Antagonists; Androstenes; Animals; Antineoplastic Agents, Hormonal; Benzamides; Cell Proliferation; Disease Progression; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Thiohydantoins

Recently, the standard of care for metastatic Castration Resistant Prostate Cancer (mCRPC) has changed considerably. Persistent androgen receptor (AR) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer. Androgen receptor gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells, making them extremely sensitive to low levels of circulating androgens. Additionally, prostate cancer cells are able to maintain dihydrotestosterone (DHT) concentration in excess of serum concentrations to support tumor growth. For many years ketoconazole was the only CYP17 inhibitor that was used to treat mCRPC. However, significant toxicities limit its use. Newly approved chemotherapeutic agents such as Abiraterone (an oral selective inhibitor of CYP17A), which blocks androgen biosynthesis both within and outside the prostate cancer cells), and enzalutamide (blocks AR signaling) have improved overall survival. There are also ongoing phase III trials for Orteronel (TAK- 700), ARN- 509 and Galeterone (TOK-001), which targets androgen signaling. In this review, we will present the rationale for the newly approved hormonal treatments, their indications and complications, and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents. Finally, we will talk about the potential upcoming hormonal treatments for mCRPC.

Topics: Abiraterone Acetate; Androgen Antagonists; Androstadienes; Androstenes; Antineoplastic Agents; Benzamides; Benzimidazoles; Combined Modality Therapy; Humans; Imidazoles; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Steroid 17-alpha-Hydroxylase; Thiohydantoins

We aim to assess the safety and efficacy of proxalutamide, a novel androgen receptor antagonist, for men with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter, randomized, open-label, phase 2 trial. In our study, the enrolled mCRPC patients were randomized to 100, 200 and 300 mg dose groups at 1:1:1. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR) and time to PSA and radiographic progression. Safety and pharmacokinetics were also assessed. Finally, there were 108 patients from 17 centers being enrolled. By week 16, there were 13 (35.1%), 12 (36.4%) and 15 (42.9%) patients with confirmed 50% or greater PSA decline in 100 mg (n = 37), 200 mg (n = 33) and 300 mg (n = 35) groups, respectively. Among the 19 patients with target lesions at study entry, three (15.8%) had a partial response and 12 (63.2%) had stable disease. The ORRs of 20.0%, 22.2%, 0% and DCRs of 80.0%, 88.9%, 60.0% were, respectively, achieved in 100, 200 and 300 mg groups. By the maximum follow-up time of 24 weeks, there were 42.6% and 10.2% of cases experiencing PSA progression and radiographic progression, respectively. Overall, adverse events (AEs) were experienced by 94.4% of patients, most of which were mild or moderate. There were 28 patients experiencing ≥grade 3 AEs. The most common AEs were fatigue (17.6%), anemia (14.8%), elevated AST (14.8%) and ALT (13.0%), decreased appetite (13.0%). These findings preliminarily showed the promising antitumor activity of proxalutamide in patients with mCRPC with a manageable safety profile. The proxalutamide dose of 200 mg daily is recommended for future phase 3 trial (Clinical trial registration no. CTR20170177).

Topics: Androgen Receptor Antagonists; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

This is a multicentre, open-label, single-arm clinical trial to evaluate the efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer.. The trial will be performed at 4 university hospitals and 14 city hospitals in Japan. The target number of patients will be 110. The patients will be orally administered 240 mg apalutamide once daily during the treatment period. The primary outcome is the prostate-specific antigen (PSA) response rate. PSA response is defined as ≥50% decline from baseline at 12 weeks. Secondary outcomes are time to PSA progression, progression-free survival, overall survival, progression-free survival during second therapy, ≥50% decline in PSA from baseline at 24 and 48 weeks, ≥90% decline in PSA from baseline or lower PSA detection sensitivity after the initial dose at 12, 24 and 48 weeks, PSA maximal changes, accumulated PSA response from screening to 24 and 48 weeks, and grade 3 or 4 adverse events according to the Common Terminology Criteria for Adverse Events version 4.0.. This study has been approved by the Certified Research Review Board of Kobe University (No. CRB5180009). All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The datasets generated during the study will be available from the corresponding author on reasonable request.. jRCTs051220077.

Topics: Humans; Male; Multicenter Studies as Topic; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

In SPARTAN, apalutamide improved metastasis-free and overall survival for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time of ≤10 mo.. We evaluated health-related quality of life (HRQoL) at the final analysis of the SPARTAN study.. Patients received apalutamide (240 mg/d) or placebo in 28-d cycles. All patients continued androgen deprivation therapy (ADT).. A total of 1207 patients with nmCRPC were randomized 2:1 to apalutamide or placebo.. HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires at day 1 of cycle 1 (predose/baseline), cycles 2-6, every two cycles during cycles 7-13, every four cycles thereafter, at the end of treatment, and every 4 mo after progression to 1  yr. Results are presented using descriptive statistics. A mixed model for repeated measures was fitted to estimate the mean scores at each scheduled visit during treatment.. At final analysis, with 52 mo follow-up for survival, the median treatment duration was 32.9 mo for apalutamide and 11.5 mo for placebo. Patients had good baseline HRQoL. At each scheduled collection during treatment, >90% per group completed the questionnaires. The change in FACT-P total score from baseline to cycles 21 and 25 significantly favored apalutamide over placebo (p = 0.0138 and 0.0009, respectively). The apalutamide group generally maintained favorable FACT-P (total and subscales) and EQ-5D-3L scores, while placebo scores tended to decline over time (starting in cycles 11-13 and pronounced by cycles 21-25). Notably, patient-reported fatigue did not worsen with apalutamide. Most patients reported being "not at all bothered" by side effects, and bother did not increase over time with apalutamide or placebo. Patients receiving apalutamide had minimal change in side-effect bother following symptomatic adverse events.. Final analysis of SPARTAN confirms that HRQoL is preserved in patients with nmCRPC receiving apalutamide plus ADT, but declines in patients receiving placebo plus ADT after approximately 1 yr.. Responses from patients with prostate cancer who were included in the SPARTAN study indicated that treatment with apalutamide, even after the most extensive follow-up time possible, did not reduce their quality of life. These results, along with improved survival and longer time to the development of metastases (reported separately), confirm the benefits of apalutamide for patients with nonmetastatic castration-resistant prostate cancer.

Topics: Androgen Antagonists; Androgens; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins

Apalutamide and darolutamide are next-generation androgen receptor inhibitors that have demonstrated superior efficacy compared to placebo in men with non-metastatic castration-resistant prostate cancer (nmCRPC) receiving androgen deprivation therapy (ADT). In the absence of head-to-head studies, the present study sought to indirectly compare the efficacy and tolerability between these two treatments.. This anchored matching-adjusted indirect comparison (MAIC) used patient-level data from the phase 3, randomized, controlled SPARTAN study (apalutamide + ADT), weighted to match aggregate published data from the ARAMIS study (darolutamide + ADT) for clinically relevant baseline measures. Hazard ratios (HR) and 95% credible intervals (CrI) were estimated for efficacy endpoints: metastasis-free survival (MFS), prostate-specific antigen (PSA) progression, progression-free survival (PFS), and overall survival (OS). Odds ratios were estimated for tolerability outcomes: adverse events and serious adverse events.. Before weighting, baseline characteristics from SPARTAN versus ARAMIS were different for median PSA (7.8 vs. 9.2 ng/mL), Eastern Cooperative Oncology Group performance status of 1 (23% vs. 31%), use of bone-targeted agents (10% vs. 4%), median time from initial diagnosis (94.9 vs. 85.4 months), and proportion of patients from North America (35% vs. 12%) and Europe (50% vs. 64%). After matching (n = 455), our analysis demonstrated that apalutamide + ADT had a Bayesian probability of being more effective than darolutamide + ADT for MFS [98.3%; HR 0.70 (95% CrI 0.51, 0.98)], PSA progression [~ 100%; HR 0.46 (95% CrI 0.33, 0.64)], and PFS [93.2%; HR 0.79 (95% CrI 0.59, 1.08)]. Results for OS and tolerability were similar between apalutamide + ADT and darolutamide + ADT.. This anchored MAIC analysis of pivotal phase 3 studies in patients with nmCRPC suggests that apalutamide + ADT is more effective than darolutamide + ADT for MFS, progression-free survival (PFS), and prostate-specific antigen (PSA) progression, with a similar OS benefit and tolerability profile.. ARAMIS ClinicalTrials.gov number: NCT02200614; SPARTAN ClinicalTrials.gov number: NCT01946204.

Topics: Androgen Antagonists; Bayes Theorem; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins

Apalutamide plus androgen deprivation therapy (ADT) significantly improved metastasis-free survival (MFS), overall survival (OS), and time to prostate-specific antigen (PSA) progression in the placebo-controlled SPARTAN study of high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).. To assess the relationships between PSA kinetics, outcomes, and molecular subtypes in SPARTAN.. The authors conducted a post hoc analysis of nmCRPC patients randomized to receive apalutamide (n = 806) or placebo (n = 401) plus ADT and a subset stratified by molecular classifiers.. Apalutamide 240 mg/d.. The association between PSA kinetics and MFS, OS, time to PSA progression, and molecular subtypes was evaluated using the landmark analysis and Kaplan-Meier methods.. By 3 mo, PSA decreased in most apalutamide-treated patients and increased in most placebo-treated patients. After apalutamide, the median time to PSA nadir, confirmed ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml were 7.4, 1.0, 1.9, and 2.8 mo, respectively. By 6 mo, 90%, 57%, and 32% of apalutamide patients had ≥50% PSA reduction, ≥90% PSA reduction, and PSA ≤0.2 ng/ml, respectively, while only 1.5% of placebo patients experienced ≥50% PSA reduction. PSA reductions were observed within 3 mo and up to 12 mo of apalutamide treatment, and were similar across molecular subtypes. Deep PSA responses (≥90% PSA reduction or PSA ≤0.2 ng/ml) at landmark 6-mo apalutamide treatment were significantly associated with improved time to PSA progression (hazard ratio {HR} [95% confidence interval {CI}] 0.25 [0.18-0.33] or 0.13 [0.08-0.21]), MFS (0.41 [0.29-0.57] or 0.3 [0.19-0.47]), and OS (0.45 [0.35-0.59] or 0.26 [0.18-0.38]; p < 0.001 for all).. Apalutamide plus ADT produced rapid, deep, and durable PSA responses by 6-mo treatment regardless of assessed molecular prognostic markers. An early PSA response with apalutamide was associated with clinical benefits, supporting prognostic value of PSA monitoring.. In this report, we describe how prostate-specific antigen (PSA) levels relate to outcomes in patients with nonmetastatic castration-resistant prostate cancer treated with apalutamide plus androgen deprivation therapy (ADT). We found that treatment with apalutamide plus ADT resulted in rapid, deep, and durable PSA responses in the majority of patients, including those with high-risk molecular subtypes, which were associated with improved survival.

Topics: Androgen Antagonists; Androgens; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

The TITAN study is a randomized, double-blind, placebo-controlled, multinational trial that evaluated apalutamide with androgen deprivation therapy in patients with metastatic castration-sensitive prostate cancer. At the first interim analysis in the Japanese subpopulation (median follow-up 25.7 months), there was an improvement in overall survival and radiological progression-free survival with apalutamide versus placebo. Here, we report the final analysis results for the Japanese subpopulation.. Patients were randomized 1:1 to receive apalutamide 240 mg or placebo. After the first interim analysis, protocol treatment was unblinded, and crossover was allowed. Efficacy and safety were evaluated in the preplanned, event-driven final analysis.. Fifty-one patients were Japanese (apalutamide n = 28; placebo n = 23). After a median follow-up of 46.0 months, the median overall survival was not reached neither in the apalutamide nor the placebo group; the hazard ratio was 0.45, favoring apalutamide, which was consistent with the overall population. Hazard ratios for time to cytotoxic chemotherapy (0.39), time to pain progression (0.87), and time to chronic opioid use (0.82) also favored apalutamide and were comparable with those of the overall population. Time to prostate-specific antigen progression and progression-free survival 2, respectively, was favored in the apalutamide group (0.21 and 0.44). Apalutamide was associated with higher incidences of rash and fracture in the Japanese subpopulation compared with the overall population.. The efficacy of apalutamide with androgen deprivation therapy in Japanese patients was consistent with efficacy demonstrated in the overall population. No new safety concerns emerged with long-term follow-up.

Topics: Androgen Antagonists; Androgens; Castration; Double-Blind Method; Humans; Japan; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Apalutamide plus androgen-deprivation therapy (ADT) has been approved for treatment of patients with metastatic castration-sensitive prostate cancer (mCSPC) based on data from phase 3 TITAN study. This analysis was conducted to describe pharmacokinetics of apalutamide and N-desmethyl-apalutamide and explore relationships between apalutamide exposure and selected clinical efficacy and safety observations.. 1052 patients were randomized to apalutamide + ADT (n = 525) or placebo + ADT (n = 527). A previously developed population pharmacokinetic model was applied. Cox regression analysis investigated the relationships between apalutamide exposure and overall survival (OS; n = 1004) and radiographic progression-free survival (rPFS; n = 1003). Logistic regression analysis assessed the relationships between apalutamide exposure and selected clinically relevant adverse events (n = 1051).. Apalutamide + ADT treatment was efficacious in extending rPFS and OS versus placebo + ADT. Within a relatively narrow apalutamide exposure range (coefficient of variation: 22%), no statistical association was detected between rPFS, OS and apalutamide exposure quartiles. Incidence of skin rash and pruritus increased significantly with increasing apalutamide exposure.. Differences in apalutamide exposure were not associated with clinically relevant differences in rPFS or OS in patients with mCSPC. Patients with increased apalutamide exposure are more likely to develop skin rash and pruritus. Dose reductions may improve these adverse events, based on an individual risk-benefit approach.

Topics: Androgen Antagonists; Castration; Exanthema; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Pruritus; Thiohydantoins

The majority of patients with metastatic castration-resistant prostate cancer (mCRPC) will have disease progression of a uniformly fatal disease. mCRPC is driven by both activated androgen receptors and elevated intratumoural androgens; however, the current standard of care is therapy that targets a single androgen signalling mechanism. We aimed to investigate the combination treatment using apalutamide plus abiraterone acetate, each of which suppresses the androgen signalling axis in a different way, versus standard care in mCRPC.. ACIS was a randomised, placebo-controlled, double-blind, phase 3 study done at 167 hospitals in 17 countries in the USA, Canada, Mexico, Europe, the Asia-Pacific region, Africa, and South America. We included chemotherapy-naive men (aged ≥18 years) with mCRPC who had not been previously treated with androgen biosynthesis signalling inhibitors and were receiving ongoing androgen deprivation therapy, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a Brief Pain Inventory-Short Form question 3 (ie, worst pain in the past 24 h) score of 3 or lower. Patients were randomly assigned (1:1) via a centralised interactive web response system with a permuted block randomisation scheme (block size 4) to oral apalutamide 240 mg once daily plus oral abiraterone acetate 1000 mg once daily and oral prednisone 5 mg twice daily (apalutamide plus abiraterone-prednisone group) or placebo plus abiraterone acetate and prednisone (abiraterone-prednisone group), in 28-day treatment cycles. Randomisation was stratified by presence or absence of visceral metastases, ECOG performance status, and geographical region. Patients, the investigators, study team, and the sponsor were masked to group assignments. An independent data-monitoring committee continually monitored data to ensure ongoing patient safety, and reviewed efficacy data. The primary endpoint was radiographic progression-free survival assessed in the intention-to-treat population. Safety was reported for all patients who received at least one dose of study drug. This study is completed and no longer recruiting and is registered with ClinicalTrials.gov, number NCT02257736.. 982 men were enrolled and randomly assigned from Dec 10, 2014 to Aug 30, 2016 (492 to apalutamide plus abiraterone-prednisone; 490 to abiraterone-prednisone). At the primary analysis (median follow-up 25·7 months [IQR 23·0-28·9]), median radiographic progression-free survival was 22·6 months (95% CI 19·4-27·4) in the apalutamide plus abiraterone-prednisone group versus 16·6 months (13·9-19·3) in the abiraterone-prednisone group (hazard ratio [HR] 0·69, 95% CI 0·58-0·83; p<0·0001). At the updated analysis (final analysis for overall survival; median follow-up 54·8 months [IQR 51·5-58·4]), median radiographic progression-free survival was 24·0 months (95% CI 19·7-27·5) versus 16·6 months (13·9-19·3; HR 0·70, 95% CI 0·60-0·83; p<0·0001). The most common grade 3-4 treatment-emergent adverse event was hypertension (82 [17%] of 490 patients receiving apalutamide plus abiraterone-prednisone and 49 [10%] of 489 receiving abiraterone-prednisone). Serious treatment-emergent adverse events occurred in 195 (40%) patients receiving apalutamide plus abiraterone-prednisone and 181 (37%) patients receiving abiraterone-prednisone. Drug-related treatment-emergent adverse events with fatal outcomes occurred in three (1%) patients in the apalutamide plus abiraterone-prednisone group (2 pulmonary embolism, 1 cardiac failure) and five (1%) patients in the abiraterone-prednisone group (1 cardiac failure and 1 cardiac arrest, 1 mesenteric arterial occlusion, 1 seizure, and 1 sudden death).. Despite the use of an active and established therapy as the comparator, apalutamide plus abiraterone-prednisone improved radiographic progression-free survival. Additional studies to identify subgroups of patients who might benefit the most from combination therapy are needed to further refine the treatment of mCRPC.. Janssen Research & Development.

Topics: Abiraterone Acetate; Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Neoplasm Metastasis; Prednisone; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Steroid Synthesis Inhibitors; Survival Rate; Thiohydantoins

The phase 3 SPARTAN study evaluated apalutamide versus placebo in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and prostate-specific antigen doubling time of ≤10 mo. At primary analysis, apalutamide improved median metastasis-free survival (MFS) by 2 yr and overall survival (OS) data were immature.. We report the prespecified event-driven final analysis for OS.. A total of 1207 patients with nmCRPC (diagnosed by conventional imaging) were randomised 2:1 to apalutamide (240mg/d) or placebo, plus on-going androgen deprivation therapy. After MFS was met and the study was unblinded, 76 (19%) patients still receiving placebo crossed over to apalutamide.. OS and time to cytotoxic chemotherapy (TTChemo) were analysed by group-sequential testing with O'Brien-Fleming-type alpha spending function.. At median 52-mo follow-up, 428 deaths had occurred. The median treatment duration was 32.9 mo for apalutamide group and 11.5 mo for placebo group. Median OS was markedly longer with apalutamide versus placebo, reaching prespecified statistical significance (73.9 vs 59.9 mo, hazard ratio [HR]: 0.78 [95% confidence interval {CI}, 0.64-0.96]; p=0.016). Apalutamide also lengthened TTChemo versus placebo (HR: 0.63 [95% CI, 0.49-0.81]; p=0.0002). Discontinuation rates in apalutamide and placebo groups due to progressive disease were 43% and 74%, and due to adverse events 15% and 8.4%, respectively. Subsequent life-prolonging therapy was received by 371 (46%) patients in the apalutamide arm and by 338 (84%) patients in the placebo arm including 59 patients who received apalutamide after crossover. Safety was consistent with previous reports; when adverse events were adjusted for treatment exposure, rash had the greatest difference of incidence between the apalutamide and placebo groups.. Extension of OS with apalutamide compared with placebo conferred impactful benefit in patients with nmCRPC. There was a 22% reduction in the hazard of death in the apalutamide group despite 19% crossover (placebo to apalutamide) and higher rates of subsequent therapy in the placebo group.. With data presented herein, all primary and secondary study end points of SPARTAN were met; findings demonstrate the value of apalutamide as a treatment option for nonmetastatic castration-resistant prostate cancer.

Topics: Aged; Cross-Over Studies; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Survival Rate; Thiohydantoins

To evaluate the efficacy and safety of apalutamide + androgen deprivation therapy versus androgen deprivation therapy alone in Japanese patients with metastatic castration-sensitive prostate cancer from the phase 3, randomized, global TITAN study.. Men with metastatic castration-sensitive prostate cancer randomly (1:1) received 240 mg apalutamide + androgen deprivation therapy or matching placebo + androgen deprivation therapy. The primary efficacy endpoints were radiographic progression-free survival and overall survival. Secondary efficacy endpoints were time to cytotoxic chemotherapy, pain progression, chronic opioid use, and skeletal-related events. Safety was also assessed.. Of the 1052 patients included in the TITAN study, 51 (4.85%) were Japanese (apalutamide group, n = 28; placebo group, n = 23). In all, 81.8% of patients in the apalutamide and 71.8% in the placebo group did not experience radiographic progression or death, and the hazard ratio for radiographic progression-free survival favored treatment with apalutamide (hazard ratio 0.712, 95% confidence interval 0.205-2.466; P = 0.59). At 24 months, 85.7% of patients in the apalutamide group and 81.5% in the placebo group were alive, and the hazard ratio for overall survival favored apalutamide (hazard ratio 0.840, 95% confidence interval 0.210-3.361; P = 0.805). In the interim analysis, the median radiographic progression-free survival and overall survival were not reached in the apalutamide group and time to cytotoxic chemotherapy was delayed following apalutamide treatment. The safety profile of apalutamide in the Japanese subpopulation was comparable with that of the global population, except for skin rash.. The results of the present analyses suggest that apalutamide + androgen deprivation therapy in Japanese patients had favorable efficacy compared with androgen deprivation therapy alone, and these findings are comparable to those in the overall population. Apalutamide + androgen deprivation therapy can be considered as one of the therapeutic options for a broad spectrum of metastatic castration-sensitive prostate cancer regardless of prior treatment and disease extent in Japanese patients.

Topics: Androgen Antagonists; Castration; Double-Blind Method; Humans; Japan; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC).. BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer.. Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib-apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation.. These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib-AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC.. NCT02924766 (ClinicalTrials.gov).

Topics: Aged; Aged, 80 and over; Androstenes; Antineoplastic Combined Chemotherapy Protocols; Humans; Indazoles; Male; Middle Aged; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Prednisone; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins

No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons.. Individual patient data from the phase III ARAMIS trial (N. No differences in metastasis-free survival hazard ratios were found after matching in either comparison. However, fall, fracture and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide.. While metastasis-free survival did not differ across drugs in these cross-trial indirect comparisons, darolutamide showed a favorable safety and tolerability profile in prespecified adverse events vs apalutamide and enzalutamide. Consideration of these adverse events is important in clinical decision-making and treatment selection in nonmetastatic castration-resistant prostate cancer.

Topics: Accidental Falls; Androgen Receptor Antagonists; Benzamides; Cognitive Dysfunction; Dizziness; Exanthema; Fatigue; Fractures, Spontaneous; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins

The first interim analysis of the phase III, randomized, placebo-controlled TITAN study showed that apalutamide significantly improved overall survival (OS) and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving ongoing androgen deprivation therapy (ADT). Herein, we report final efficacy and safety results after unblinding and placebo-to-apalutamide crossover.. Patients with mCSPC (N = 1,052) were randomly assigned 1:1 to receive apalutamide (240 mg QD) or placebo plus ADT. After unblinding in January 2019, placebo-treated patients were allowed to receive apalutamide. Efficacy end points were updated using the Kaplan-Meier method and Cox proportional-hazards model without formal statistical retesting and adjustment for multiplicity. Change from baseline in Functional Assessment of Cancer Therapy-Prostate total score was assessed.. With a median follow-up of 44.0 months, 405 OS events had occurred and 208 placebo-treated patients (39.5%) had crossed over to apalutamide. The median treatment duration was 39.3 (apalutamide), 20.2 (placebo), and 15.4 months (crossover). Compared with placebo, apalutamide plus ADT significantly reduced the risk of death by 35% (median OS not reached. The final analysis of TITAN confirmed that, despite crossover, apalutamide plus ADT improved OS, delayed castration resistance, maintained health-related quality of life, and had a consistent safety profile in a broad population of patients with mCSPC.

Topics: Androgen Receptor Antagonists; Disease Progression; Double-Blind Method; Humans; Male; Neoplasm Metastasis; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins; Time Factors

There is a need to identify prognostic biomarkers to guide treatment intensification in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC).. To examine whether molecular subtypes predict response to apalutamide, using archived primary tumor samples from the randomized, double-blind, phase 3 SPARTAN trial.. In this cohort study, gene expression data from 233 archived samples from patients with nmCRPC enrolled in the SPARTAN trial were generated using a human exon microarray. The present analysis was conducted from May 10, 2018, to October 15, 2020.. Patients were randomized (2:1) to apalutamide, 240 mg/d, with androgen deprivation therapy (apalutamide+ADT) or placebo+ADT.. Patients were stratified into high-risk and low-risk categories for developing metastases based on genomic classifier (GC) scores for high (GC >0.6) and low to average (GC≤0.6) and into basal and luminal subtypes; associations between these molecular subtypes and metastasis-free survival (MFS), overall survival (OS), and progression-free survival 2 (PFS2) were evaluated using Cox proportional hazards regression and Kaplan-Meier analysis.. Median age of the 233 included patients was 73 (range, 49-91) years. A total of 116 of 233 patients (50%) in the SPARTAN biomarker subset had high GC scores. Although all patients receiving apalutamide+ADT had improved outcomes, having high GC scores was associated with the greatest improvement in MFS (hazard ratio [HR], 0.21; 95% CI, 0.11-0.40; P < .001), OS (HR, 0.52; 95% CI, 0.29-0.94; P = .03), and PFS2 (HR, 0.39; 95% CI, 0.23-0.67; P = .001) vs placebo+ADT. In total, 152 of 233 patients (65%) had the basal molecular subtype. Although there were no significant differences in MFS, PFS2, or OS between patients with the luminal vs basal subtype in the placebo+ADT arm, patients with the luminal subtype in the apalutamide+ADT arm had a significantly longer MFS (apalutamide+ADT: HR, 0.40; 95% CI, 0.18-0.91; P = .03; placebo+ADT: HR, 0.66; 95% CI, 0.33-1.31; P = .23) compared with patients with basal subtype; similar trends were observed for OS (apalutamide+ADT: HR, 0.50; 95% CI, 0.25-0.98; P = .04; placebo+ADT: HR, 0.78; 95% CI, 0.38-1.60; P = .50), and PFS2 (apalutamide+ADT: HR, 0.71; 95% CI, 0.42-1.22; P = .22; placebo+ADT: HR, 0.72; 95% CI, 0.38-1.39; P = .33). In regression analysis, the luminal-basal subtype score was significantly associated with MFS in patients receiving apalutamide+ADT (HR, 2.65; 95% CI, 1.15-6.08; P = .02), whereas GC score was significantly associated with MFS in placebo+ADT recipients (HR, 2.09; 95% CI, 1.02-4.27; P = .04).. The findings of this study suggest that the GC score and basal-luminal subtype derived from archived tumor specimens may be biomarkers of response to apalutamide+ADT in the nmCRPC setting. Although overall, the addition of apalutamide to ADT was beneficial, higher-risk and luminal subtypes appeared to benefit most. Obtaining GC scores may be useful for identifying patients for early treatment intensification with apalutamide, and basal-luminal subtyping may be a beneficial approach for patient selection for further treatment intensification in trials combining novel therapies with apalutamide.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Androgen Receptor Antagonists; Cohort Studies; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

Two phase I studies assessed the drug-drug interaction potential of apalutamide as a substrate and perpetrator.. Study A randomized 45 healthy men to single-dose apalutamide 240 mg alone or with strong inhibitors of cytochrome P450 (CYP)3A4 (itraconazole) or CYP2C8 (gemfibrozil). In study B, 23 patients with castration-resistant prostate cancer received probes for CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP2C8 (pioglitazone), and transporter substrates for P-glycoprotein (P-gp) (fexofenadine) and breast cancer resistance protein (BCRP)/organic anion transporting polypeptide (OATP) 1B1 (rosuvastatin) at baseline and after repeat once-daily administration of apalutamide 240 mg to steady state.. Systemic exposure (area under the plasma concentration-time curve) to single-dose apalutamide increased 68% with gemfibrozil but was relatively unchanged with itraconazole (study A). Apalutamide reduced systemic exposure to midazolam ↓92%, omeprazole ↓85%, S-warfarin ↓46%, fexofenadine ↓30%, rosuvastatin ↓41%, and pioglitazone ↓18% (study B). After a single dose, apalutamide is predominantly metabolized by CYP2C8, and less by CYP3A4.. Co-administration of apalutamide with CYP3A4, CYP2C19, CYP2C9, P-gp, BCRP or OATP1B1 substrates may cause loss of activity for these medications. Therefore, appropriate mitigation strategies are recommended.

Topics: Cytochrome P-450 Enzyme Inhibitors; Drug Interactions; Humans; Male; Neoplasm Proteins; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone (AA-P) in patients with metastatic CRPC (mCRPC).. Multicenter, open-label, phase Ib drug-drug interaction study conducted in 57 patients with mCRPC treated with 1,000 mg abiraterone acetate plus 10 mg prednisone daily beginning on cycle 1 day 1 (C1D1) and 240 mg apalutamide daily starting on C1D8 in 28-day cycles. Serial blood samples for pharmacokinetic analysis were collected on C1D7 and C2D8.. Systemic exposure to abiraterone, prednisone, and prednisolone decreased 14%, 61%, and 42%, respectively, when apalutamide was coadministered with AA-P. No increase in mineralocorticoid excess-related adverse events was observed. Patients without prior exposure to AR signaling inhibitors had longer median treatment duration and greater mean decrease in prostate-specific antigen (PSA) from baseline compared with those who had received prior therapy. Confirmed PSA reductions of ≥50% from baseline at any time were observed in 80% (12/15) of AR signaling inhibitor-naïve patients and 14% (6/42) of AR signaling inhibitor-treated patients.. Treatment with apalutamide plus AA-P was well tolerated and showed evidence of antitumor activity in patients with mCRPC, including those with disease progression on AR signaling inhibitors. No clinically significant pharmacokinetic interaction was observed between abiraterone and apalutamide; however, apalutamide decreased exposure to prednisone. These data support development of 1,000 mg abiraterone acetate plus 10 mg prednisone daily with 240 mg apalutamide daily in patients with mCRPC.

Topics: Abiraterone Acetate; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cross-Over Studies; Drug Administration Schedule; Drug Interactions; Humans; Kallikreins; Male; Middle Aged; Prednisone; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

We conducted preclinical experiments and phase I clinical trial to investigate the safety, pharmacokinetics (PK) and antitumour effects of GT0918 in castration-resistant prostate cancer (CRPC).. An androgen receptor (AR) competitive binding assay was performed, followed by evaluation of GT0918 on AR protein expression. The efficacy of GT0918 was investigated in a castration-resistant xenograft model. A phase I dose-escalation study of GT0918 in CRPC was also carried out to evaluate its safety, PK and antitumour efficacy.. GT0918 was demonstrated to inhibit the binding of androgen to AR more potently than MDV3100, and to effectively reduce the AR protein level. GT0918 inhibited the transcriptional activity of wild-type AR and AR with clinically relevant ligand-binding domain mutations. Furthermore, GT0918 significantly inhibited the growth of prostate cancer. A total of 16 patients was treated with GT0918 at five dose levels. Among these 16 patients, 10 and 2 patients, respectively, completed a three-cycle and six-cycle treatment, in which MTD was not reached. All the treatment-related adverse events were grade I, including hypercholesterolemia, hypertriglyceridemia, fatigue and anaemia. PK parameters showed that drug exposure increased with dose proportionally from 50 to 300 mg and a saturation was observed between 300 and 400 mg. PSA declines of ≥30% and ≥50% were, respectively, observed in six and two cases. All the 12 patients with metastatic soft tissue lesions confirmed stable disease.. GT0918, a full AR antagonist without agonist effect, has high binding affinity to AR with AR protein down-regulation activity. GT0918 is demonstrated to be well tolerated with a favourable PK profile and exhibits promising antitumour activity in CRPC. CLINICALTRIALS: gov identifier CTR20150501.

Topics: Aged; Animals; Apoptosis; Cell Proliferation; Follow-Up Studies; Humans; Male; Maximum Tolerated Dose; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Oxazoles; Prognosis; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Tissue Distribution; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer.. An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia.. A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure.. The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events.

Topics: Adult; Androgen Receptor Antagonists; Area Under Curve; Dose-Response Relationship, Drug; Drug Eruptions; Humans; Male; Middle Aged; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Weight Loss

A higher incidence of apalutamide-related skin rash has been observed in Japanese patients with prostate cancer (PC).. This integrated analysis of data of Japanese patients from 2 global Phase 3 studies, SPARTAN ( NCT01946204 ; patients with non-metastatic castration-resistant PC [nmCRPC]) and TITAN ( NCT02489318 ; patients with metastatic castration-sensitive PC [mCSPC]), and the Phase 1 study 56021927PCR1008 ( NCT02162836 ; patients with metastatic CRPC [mCRPC]), assessed clinical risk factors of apalutamide-related skin rash as well as the potential correlation with plasma exposure to apalutamide. Kaplan-Meier method was used for time-to-event analyses. Clinical risk factors for skin rash were assessed using odds ratio.. Data from 68 patients (SPARTAN: n = 34, TITAN: n = 28, 56021927PCR1008: n = 6) receiving apalutamide 240 mg orally once-daily were analyzed. Rash (13 [19.1%]) and maculo-papular rash (11 [16.2%]) were the most frequently reported skin rash. All Grade and Grade 3 skin rash occurred in 35 (51.5%) and 10 (14.7%) patients, respectively. Most (85.7%) skin rash occurred within 4 months of apalutamide initiation and resolved in a median time of 1 month following the use of antihistamines, topical or systemic corticosteroids, with/without apalutamide dose interruptions/reductions. Median time-to-remission of first incidence of rash and maximum grade incidence of rash were 1.0 month (IQR: 0.36-1.81) and 1.0 month (IQR: 0.30-2.43), respectively. No significant clinical risk factors for the incidence of skin rash were observed. Areas under the curve (0-24 h) (AUC. No clinical risk factors for rash could be detected. There is a potential correlation between incidence of skin rash and plasma exposure to apalutamide. In general, apalutamide-related skin rash is easily managed, with appropriate treatment with or without dose adjustment.. Retrospective pooled analysis of NCT01946204 , NCT02489318 , and NCT02162836 .

Topics: Aged; Double-Blind Method; Drug Eruptions; Exanthema; Humans; Japan; Male; Middle Aged; Neoplasm Staging; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Thiohydantoins

Apalutamide, a nonsteroidal potent androgen receptor antagonist, was safe and effective in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and metastatic-CRPC (mCRPC) in global studies. In this phase 1 study, safety, pharmacokinetics (PK), and efficacy of apalutamide were evaluated in Japanese patients with mCRPC.. In this open-label, multi-center study, patients received apalutamide 240 mg (once-daily, orally) for first 1 week (PK week) during which PK parameters were assessed. 1 week later (Cycle 1 Day1), after reassessing safety, continuous daily dosing (4 weeks/cycle; once-daily orally) was initiated. Endpoints evaluated were: safety, tolerability, PK and antitumour efficacy of apalutamide. Dose-limiting toxicities (DLTs) were evaluated during PK week and Cycle 1.. Apalutamide had manageable safety profile, without any DLT or any new safety signals, and favourable efficacy in Japanese mCRPC patients. Thus, it was ascertained to be an adequate dosage regimen in Japanese mCRPC patients.. ClinicalTrials.gov identifier: NCT02162836.

Topics: Administration, Oral; Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Agents; Exanthema; Humans; Japan; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2).. One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed.. Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed.. In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Topics: Androgen Receptor Antagonists; Cross-Over Studies; Disease Progression; Humans; Male; Middle Aged; Placebos; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Time Factors

In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue.. In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days -6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1-7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing.. Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0-10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0-3·17) in the apalutamide group and 1·00 (0-2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0-3·29) in the apalutamide group and 1·43 (0·14-3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04-not reached) in the apalutamide group versus 11·99 months (8·28-18·46) in the placebo group (HR 0·89 [95% CI 0·75-1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58-not reached in the apalutamide group; not reached-not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55-11·96) in the apalutamide group and 6·24 months (4·63-7·43) in the placebo group (HR 0·90 [95% CI 0·73-1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70-11·10) in the apalutamide group and 9·23 months (7·39-12·91) in the placebo group (HR 1·02 [95% CI 0·85-1·22]; p=0·85).. Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade.. Janssen Research & Development.

Topics: Aged; Androgen Antagonists; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Asia; Chemotherapy, Adjuvant; Disease Progression; Europe; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; North America; Orchiectomy; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Quality of Life; South America; Thiohydantoins; Time Factors

Testosterone suppression is the standard treatment for advanced prostate cancer, and it is associated with side-effects that impair patients' quality of life, like sexual dysfunction, osteoporosis, weight gain, and increased cardiovascular risk. We hypothesized that abiraterone acetate with prednisone (AAP) and apalutamide, alone or in combination, can be an effective hormonal therapy also possibly decreasing castration-associated side effects.. Phase II, open-label, randomized, efficacy trial of abiraterone acetate plus prednisone (AAP) and Androgen Deprivation Therapy (ADT) versus apalutamide versus the combination of AAP (without ADT) and apalutamide. Key eligibility criteria are confirmed prostate adenocarcinoma; biochemical relapse after definitive treatment (PSA ≥ 4 ng/ml and doubling time less than 10 months, or PSA ≥ 20 ng/ml); newly diagnosed locally advanced or metastatic prostate cancer; asymptomatic to moderately symptomatic regarding bone symptoms. Patients with other histology besides adenocarcinoma or previous use of hormonal therapy or chemotherapy were excluded.. There is an urgent need to study and validate regimens such as new hormonal agents that may add benefit to castration with an acceptable safety profile. We aim to evaluate if apalutamide in monotherapy or in combination with AAP is an effective and safety hormonal treatment that can spare patients of androgen deprivation therapy.. This trial was registered in ClinicalTrials.gov on October 16, 2017, under Identifier: NCT02867020.

Topics: Abiraterone Acetate; Adenocarcinoma; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Goserelin; Humans; Male; Patient Reported Outcome Measures; Prednisone; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Testosterone; Thiohydantoins; Treatment Outcome

Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis.. We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death.. A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%).. Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Androgen Antagonists; Disease Progression; Disease-Free Survival; Double-Blind Method; Exanthema; Humans; Male; Middle Aged; Neoplasm Metastasis; Proportional Hazards Models; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Topics: Germany; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed.. Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day - 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety.. Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1-2 in severity. No patients discontinued due to QTc prolongation or AEs.. The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Electrocardiography, Ambulatory; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

In the SPARTAN trial, addition of apalutamide to androgen deprivation therapy, as compared with placebo plus androgen deprivation therapy, significantly improved metastasis-free survival in men with non-metastatic castration-resistant prostate cancer who were at high risk for development of metastases. We aimed to investigate the effects of apalutamide versus placebo added to androgen deprivation therapy on health-related quality of life (HRQOL).. SPARTAN is a multicentre, international, randomised, phase 3 trial. Participants were aged 18 years or older, with non-metastatic castration-resistant prostate cancer, a prostate-specific antigen doubling time of 10 months or less, and a prostate-specific antigen concentration of 2 ng/mL or more in serum. Patients were randomly assigned (2:1) to 240 mg oral apalutamide per day plus androgen deprivation therapy, or matched oral placebo plus androgen deprivation therapy, using an interactive voice randomisation system. Permuted block randomisation was used according to the three baseline stratification factors: prostate-specific antigen doubling time (>6 months vs ≤6 months), use of bone-sparing drugs (yes vs no), and presence of local-regional nodal disease (N0 vs N1). Each treatment cycle was 28 days. The primary endpoint was metastasis-free survival. The trial was unblinded in July, 2017. In this prespecified exploratory analysis we assessed HRQOL using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires, which we collected at baseline, day 1 of cycle 1 (before dose), day 1 of treatment cycles 1-6, day 1 of every two cycles from cycles 7 to 13, and day 1 of every four cycles thereafter. This study is registered with ClinicalTrials.gov, number NCT01946204.. Between Oct 14, 2013, and Dec 15, 2016, we randomly assigned 1207 patients to receive apalutamide (n=806) or placebo (n=401). The clinical cutoff date, as for the primary analysis, was May 19, 2017. Median follow-up for overall survival was 20·3 months (IQR 14·8-26·6). FACT-P total and subscale scores were associated with a preservation of HRQOL from baseline to cycle 29 in the apalutamide group; there were similar results for EQ-5D-3L. At baseline, the mean for FACT-P total score in both the apalutamide and placebo groups were consistent with the FACT-P general population norm for US adult men. Group mean patient-reported outcome scores over time show that HRQOL was maintained from baseline after initiation of apalutamide treatment and was similar over time among patients receiving apalutamide versus placebo. Least-squares mean change from baseline shows that HRQOL deterioration was more apparent in the placebo group.. In asymptomatic men with high-risk non-metastatic castration-resistant prostate cancer, HRQOL was maintained after initiation of apalutamide treatment. Considered with findings from SPARTAN, patients who received apalutamide had longer metastasis-free survival and longer time to symptomatic progression than did those who received placebo, while preserving HRQOL.. Janssen Research & Development.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Agents; Humans; Kallikreins; Male; Neoplasm Metastasis; Patient Reported Outcome Measures; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins; Time Factors

Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients.. Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH).. Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months.. The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide.. NCT01171898.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Circulating Tumor DNA; Humans; Male; Middle Aged; Point Mutation; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Double-Blind Method; Germany; Humans; Male; Middle Aged; Neoplasm Metastasis; Placebo Effect; Prevalence; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Survival Rate; Thiohydantoins; Treatment Outcome

Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets.. To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC).. We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo).. Patients received 240mg/d apalutamide while continuing on androgen-deprivation therapy.. Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS).. A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data.. In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control.. Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting.. ClinicalTrials.gov identifier NCT01171898.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Disease-Free Survival; Humans; Kallikreins; Male; Middle Aged; Neoplasm Grading; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

Apalutamide is an oral selective androgen receptor inhibitor, approved by the FDA for the treatment of patients with non-metastatic, castration-resistant prostate cancer (M0 CRPC) at high risk of developing metastases and for patients with metastatic castration-sensitive prostate (mHSPC) in association with androgen deprivation therapy (ADT). In the registration studies, skin reactions were reported among the most common side effects and as an adverse event of special interest.. Apalutamide-induced rash includes a wide spectrum of different types of skin reactions, but few cases reports and case series have described this adverse event. Here, we report an M0 CRPC patient who experienced a rare skin adverse event, a lichenoid reaction.. After 4 months of therapy with apalutamide, the patient reported dorsal pricking and dry skin. Lichenoid reaction was confirmed histologically and its correlation to the drug was demonstrated after pursuing a multidisciplinary approach.. To our knowledge, this is one of the first cases of Apalutamide-related lichenoid reaction and this clinical case showed the relevance of a multidisciplinary management when assessing drug-related adverse events. A broader knowledge of the spectrum of drug-related reactions would allow for a better diagnosis and therapy management by both physicians and patients.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC.. LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide).. The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes.. Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.

Topics: Androgen Receptor Antagonists; Animals; Benzamides; Cell Count; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Signal Transduction; Simvastatin; Thiohydantoins; Tissue Array Analysis; Xenograft Model Antitumor Assays

Topics: Body Size; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Thiohydantoins

Second-generation androgen receptor inhibitors (ARIs) have been associated with adverse events (AEs) such as fatigue, falls, fractures, and rash in non-metastatic castration-resistant prostate cancer (nmCRPC) patients as identified in clinical trials. The objectives of this study were to describe the incidence and management of AEs in patients receiving apalutamide and enzalutamide.. This retrospective chart review study was conducted in nmCRPC-treating sites in the United States. Patients starting apalutamide or enzalutamide between February 1, 2018 and December 31, 2018 were included and any AEs they experienced were recorded. AEs, including those considered to be of special interest as defined in the pivotal clinical trials of the second-generation ARIs, were analyzed and grouped retrospectively in this study. Detailed chart data (patient demographics, clinical characteristics, treatment history, type of AE, outcomes, and resource utilization) were then collected for a randomly selected subset among patients with ≥1 AE to characterize AEs and their management. Descriptive results were summarized.. Forty-three sites participated in the study. A total of 699 patients were included, of whom 525 (75.1%) experienced ≥1 AE. The most common AEs were fatigue/asthenia (34.3%), hot flush (13.9%), and arthralgia (13.6%). In the subset of 250 patients randomly selected from those who experienced ≥1 AE, patients were primarily White (72.0%), the mean age was 71 years, 86.0% had an Eastern Cooperative Oncology Group score of 0-1 at nmCRPC diagnosis, and the average prostate specific antigen (PSA) value at diagnosis was 23.2 ng/mL. PSA-doubling time < 10 months was chosen as reason to initiate treatment in 40% of patients. The median duration of follow-up was 1.1 years, with 14.4% of patients progressing to metastasis by end of study period. Grade 3-4 and Grade 5 AEs occurred in 14.4 and 0.4% of patients, respectively. Actions taken to manage AEs included AE-directed treatment (38.0%), ARI discontinuation (10.4%), dose reduction (7.6%), and AE-related hospitalization (4.8%).. This study highlights the burden of AEs among nmCRPC patients treated with apalutamide or enzalutamide, providing a relevant real-world benchmark as clinical trial evidence and the treatment landcape for nmCRPC continues to evolve.

Topics: Aged; Androgen Receptor Antagonists; Antineoplastic Agents, Hormonal; Arthralgia; Asthenia; Benzamides; Fatigue; Flushing; Hospitalization; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Thiohydantoins; United States

To describe prostate-specific antigen (PSA) response and treatment adherence, overall and stratified by race, for patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide.. Electronic medical records representing 63 urology practices from the United States were used to conduct this study. Patients with ≥2 apalutamide prescription fills and ≥12 months of prior prostate cancer management were identified. Patients were followed from apalutamide initiation until a switch to another antineoplastic treatment, death, or end of data availability (October 4, 2019). PSA response (≥50% decline from baseline PSA) and apalutamide adherence rates are described for the overall nmCRPC population treated and also stratified by race (Black and non-Black cohorts).. Overall, 193 patients with nmCRPC were initiated on apalutamide. Thirty-three patients were Black (17.1%), 138 were non-Black (71.5%), and the remaining had an unknown racial background. The mean baseline PSA level for the overall, Black, and non-Black cohorts, was 7.0 ng/mL, 10.5 ng/mL, and 5.6 ng/mL, respectively. At 12 months of follow-up, PSA response was 86.0%, 93.1%, and 85.9% for the overall, Black, and non-Black cohorts, respectively. During a mean follow-up period of 333 days, 352 days, and 326 days, adherence was 93.6%, 90.1%, and 94.5% for the overall, Black and non-Black cohorts, respectively.. This real-world study of patients with nmCRPC initiated on apalutamide showed that PSA response was robust and consistent with clinical trial data. Moreover, both Black and non-Black patients demonstrated high treatment adherence.

Topics: Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Adherence and Compliance

Therapeutic strategies for prostate cancer are currently undergoing a paradigm shift due to the advent of next-generation androgen receptor inhibitors. Among these inhibitors, apalutamide is regarded as a key drug because of its effectiveness. However, risk factors for and the timing of the onset of apalutamide-related cutaneous adverse events remain unclear. Therefore, the present study investigated key risk factors for and timing of the onset of apalutamide-related cutaneous adverse events.. Sixty-two Japanese patients with non-metastatic castration-resistant prostate cancer treated with 240 mg/day of apalutamide were enrolled in the present study.. Twenty-four patients (38.7%) developed cutaneous adverse events. Multivariable logistic regression analysis of age, height, and body weight identified body weight as a significant predictive factor for the incidence of cutaneous adverse events (p=0.019). When the mean body weight of patients (63.80 kg) was set as the cut-off value, the Kaplan-Meier analysis revealed that the risk of cutaneous adverse events was significantly increased in those with a body weight <63.8 kg (p=0.003, the log-rank test). The analysis also showed that cutaneous adverse events developed within the first 6 months regardless of body weight.. A lower body weight is a significant risk factor for apalutamide-related cutaneous adverse events and their onset is within 6 months of initiation of therapy.

Topics: Body Weight; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Risk Factors; Thiohydantoins

Apalutamide-associated skin adverse events are more common in the Japanese than in the global population. However, limited clinical data have hampered further understanding. This real-world study investigated the clinical characteristics of skin adverse events in patients with advanced prostate cancer.. We retrospectively reviewed 119 patient records from 16 institutions in Japan. Skin adverse events were graded according to the Common Terminology Criteria for Adverse Events (v5.0). The incidence and characteristics of skin adverse events (along with the clinical risk factors for their incidence, worsening, and recurrence) were evaluated.. Fifty-five patients (46.2%) experienced skin adverse events. The median times to the incidence and remission of skin adverse events were 62 and 30 days, respectively. Grade 3 skin adverse events were observed in 15 patients (12.6%). The median time from the first incidence to apalutamide interruption was significantly longer in patients with progression to grade 3 skin adverse events than in those without such a progression (8 vs. 0 days, p = 0.005). Skin adverse events were observed in 45.2% of patients who resumed apalutamide treatment (median treatment interruption time: 31.5 days). Sixteen patients (13.4%) permanently discontinued apalutamide due to skin adverse events. No significant clinical risk factors for the incidence, worsening and recurrence of apalutamide-associated skin adverse events were observed.. Nearly half of the Japanese patients in this study experienced skin adverse events following apalutamide administration. The time to apalutamide discontinuation after the incidence of skin adverse events was positively correlated with the worsening of these events.

Topics: Androgen Receptor Antagonists; Humans; Japan; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Thiohydantoins

Topics: Humans; Male; Neoadjuvant Therapy; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Androgen-deprivation therapy (ADT), either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone analogue agonist or antagonist, is the mainstay of treatment for advanced prostate cancer. In the metastatic setting, although ADT is initially effective, castration-resistant disease eventually develops in almost all men with prostate cancer. Since 2015, the addition of docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide with docetaxel to ADT has been shown to improve overall survival (OS) of patients starting ADT for metastatic disease. Castration resistance occurs when disease progresses despite testosterone in the castrate range most commonly with or, more rarely, without detectable metastases. The addition of next-generation antiandrogens to ADT has been shown to improve OS in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) identified by a PSA doubling time (DT) ? 10 months. Apalutamide is a nonsteroidal antiandrogen agent that binds directly to the ligand-binding domain of the androgen receptor without agonist activity. When added to ADT apalutamide has been shown to improve OS by 35 % in patients starting ADT for metastatic prostate cancer both in patients with upfront metastatic disease or after previous treatment with curative intent. Similarly apalutamide has been shown to provide a 14-month OS improvement in patients with nmCRPC and short PSA DT. These OS benefits were obtained at no cost in terms of quality of life. Apalutamide is given orally once a day and is well tolerated. The most common side effects are fatigue, rash, hypertension and hot flushes. Potential interactions with concomitant medication should be taken into account.. La privation androgénique, chimique au moyen d’agonistes ou d’antagonistes de la LHRH, ou chirurgicale par orchidectomie, est un élément essentiel du traitement du cancer de la prostate avancé. Chez les patients métastatiques, son efficacité est cependant transitoire et une progression survient invariablement. Depuis 2015, une amélioration de la survie des patients métastatiques devant débuter une privation androgénique a été démontrée par l’instauration précoce soit d’une chimiothérapie par docétaxel, soit d’une hormonothérapie de nouvelle génération telle que l’abiratérone, l’enzalutamide, l’apalutamide, voire un traitement combinant docétaxel et darolutamide. Lorsque les patients progressent en dépit de la privation androgénique, on les dit résistants à la castration, le plus souvent en présence de métastases mais parfois en l’absence de lésion secondaire identifiable. Dans le cas des patients non métastatiques résistant à la castration à risque élevé d’évolution défavorable en raison d’un temps de doublement du PSA ? 10 mois, on a également démontré que l’ajout d’un anti-androgène de nouvelle génération améliorait la survie globale des patients. L’apalutamide, ou Erleada®, est un inhibiteur sélectif du récepteur aux androgènes, sans activité agoniste, administré par voie orale. Son instauration, en même temps que la privation androgénique, permet de réduire de 35 % la mortalité des patients métastatiques d’emblée ou secondairement après un traitement initial à visée curative. De même, l’apalutamide permet d’augmenter de 14 mois la survie des patients non métastatiques résistant à la castration à risque élevé d’évolution défavorable. Ces améliorations de la survie globale ont été obtenues sans détérioration de la qualité de vie. L’Erleada® est globalement bien toléré, et facile à administrer, s’agissant d’une prise orale unique quotidienne. La fatigue, la toxicité cutanée souvent modérée, l’hypertension artérielle et les bouffées de chaleur sont les effets secondaires les plus fréquents. Il convient également d’être attentif aux interactions médicamenteuses potentielles.

Topics: Androgen Antagonists; Androgens; Docetaxel; Gonadotropin-Releasing Hormone; Humans; Ligands; Male; Nonsteroidal Anti-Androgens; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Receptors, Androgen; Testosterone; Thiohydantoins

The occurrence of distant metastases represents a prognostically unfavourable turning point in non-metastatic castration-resistant prostate cancer (M0CRPC). M0CRPC patients with a short PSA doubling time have a particularly high risk of progression. For a long time, there was no further treatment option for these patients apart from watchful waiting while maintaining classic androgen deprivation therapy (ADT). Apalutamide, a next-generation anti-androgen available since January 2019, significantly increased metastasis-free survival compared with placebo in the pivotal SPARTAN trial in patients with high-risk M0CRPC. The presented patient cases from SPARTAN and the apalutamide compassionate use program are examples of the beneficial effects that apalutamide can achieve in the M0CRPC setting.. Das Auftreten von Fernmetastasen stellt beim nicht fernmetastasierten kastrationsresistenten Prostatakarzinom (M0CRPC) einen prognostisch ungünstigen Wendepunkt dar. Dabei haben M0CRPC-Patienten mit kurzer PSA-Verdopplungszeit ein besonders hohes Progressionsrisiko. Für diese Patienten gab es lange Zeit, bis auf das abwartende Beobachten unter Beibehaltung der klassischen Androgendeprivationstherapie (ADT), keine weiteren Therapieoptionen. Das seit Januar 2019 verfügbare Next-Generation Antiandrogen Apalutamid verlängerte in der Zulassungsstudie SPARTAN beim Hochrisiko-M0CRPC das metastasenfreie Überleben signifikant gegenüber Placebo. Die vorliegenden Patientenfälle aus der SPARTAN-Studie und dem Apalutamid Härtefallprogramm sind Beispiele für die positiven Effekte, die Apalutamid im M0CRPC-Stadium erzielen kann.

Topics: Androgen Antagonists; Compassionate Use Trials; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Prostate cancer progresses, despite androgen-deprivation therapy, the backbone of its treatment. This progression is mainly related to the androgen receptor (AR)-related mechanisms of resistance, and, several AR-targeted therapies have demonstrated benefit in metastatic and nonmetastatic disease. Apalutamide is a third-generation AR-targeted therapy which competitively blocks the AR and prevents AR dimerization, nuclear internalization, thereby avoiding cancer progression. Early studies have demonstrated that apalutamide was safe and demonstrated clinical benefit. Phase II and phase III studies had confirmed preliminary results of clinical benefit with apalutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and in metastatic hormone-sensitive prostate cancer (mHSPC).. Herein, the authors discuss the development of apalutamide, from its discovery and early studies to phase III trials. They also examine new perspectives and biomarkers that may help oncologists to make decisions in patients taking apalutamide. Studies evaluating apalutamide in other settings and in combination with other therapies are also debated.. Apalutamide has become a relevant therapy for patients with nmCRPC and mHSPC for its benefit in delaying metastasis in addition to its improvement of overall survival, without compromising the quality of life. Apalutamide should be considered as a standard-of-care for patients with nmCRPC and patients with mHSPC.

Topics: Androgen Receptor Antagonists; Biomarkers, Tumor; Drug Development; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Survival Rate; Thiohydantoins

The TITAN study, which compares apalutamide plus ADT with placebo plus ADT in an all-comers population of patients with metastatic hormone-sensitive prostate cancer (mHSPC), reached both primary endpoints, rPFS and OS, at the first planned interim analysis 1. After a median follow-up of 22.7 months, the risk of radiographic progression was reduced by 52 % (p < 0.001) 1. The rPFS benefit was observed in all subgroups and independently of tumour burden or docetaxel pre-treatment 1. The OS interim analysis showed a mortality risk reduced by 33 % in favour of apalutamide plus ADT (p = 0.0053) 1. The secondary endpoint of time to cytotoxic chemotherapy as well as the exploratory endpoints of time to PSA progression and second progression-free survival (PFS2), defined as time between randomisation and second disease progression or death under the first subsequent therapy, were also significantly improved 1 2. Overall, apalutamide showed good tolerability, with a higher rate of apalutamide-typical rash and hypothyroidism but no relevant increase in fatigue, falls or fractures compared with placebo, and with quality of life being maintained 1. Apalutamide plus ADT can thus be an effective and well-tolerated new treatment option in many patients with mHSPC.. Die TITAN-Studie zum Vergleich von Apalutamid plus ADT mit Placebo plus ADT in einer breiten, sog. „all-comers“ Patientenpopulation mit metastasiertem hormonsensitivem Prostatakarzinom (mHSPC) erreichte bereits bei der ersten geplanten Interimsanalyse beide koprimären Endpunkte rPFS und OS 1. Nach einer medianen Nachbeobachtungszeit von 22,7 Monaten war das radiographische Progressionsrisiko um 52 % statistisch signifikant reduziert (p < 0,001) 1. Dabei war der rPFS-Vorteil in allen Subgruppen und unabhängig von der Tumorlast oder einer Docetaxel-Vorbehandlung zu beobachten 1. Die OS-Interimsanalyse zeigte statistisch signifikant ein um 33 % verringertes Mortalitätsrisiko zugunsten von Apalutamid plus ADT (p = 0,0053) 1. Signifikant verbessert waren auch der sekundäre Endpunkt Zeit bis zur zytotoxischen Chemotherapie (p < 0,0001) sowie die explorativen Endpunkte Zeit bis zur PSA-Progression und PFS2, definiert als Zeit zwischen Randomisierung und der zweiten Progression bzw. Tod unter der ersten Folgetherapie 1 2. Apalutamid wurde von den Patienten insgesamt gut vertragen. Neben einem erhöhten Auftreten von Apalutamid-typischen Hautausschlägen und Hypothyreose wurde in TITAN im Vergleich zu Placebo keine relevante Zunahme anderer Nebenwirkungen von speziellem Interesse wie Fatigue, Stürze und Frakturen beobachtet, und auch die Lebensqualität blieb erhalten 1. Damit kann Apalutamid plus ADT bei einer All-comers-Population mit mHSPC eine effektive und gut verträgliche neue Therapieoption darstellen.

Topics: Androgen Antagonists; Hormones; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins

Topics: Androgen Antagonists; Benzamides; Budgets; Cost Savings; Drug Costs; Humans; Male; Models, Economic; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Thiohydantoins; United States

Amplifications of the androgen receptor (AR) occur in up to 80% of men with castration-resistant prostate cancer (CRPC). Recent studies highlighted that these amplifications not only span the AR gene but usually encompass a distal enhancer. This represents a newly recognised, non-coding mechanism of resistance to AR-directed therapies, including enzalutamide. To study disease progression before and after AR amplification, we used tumour samples from a castrate-sensitive primary tumour and castrate-resistant metastasis of the same patient. For subsequent functional and genomic studies, we established serially transplantable patient-derived xenografts (PDXs). Whole genome sequencing showed that alterations associated with poor prognosis, such as TP53 and PTEN loss, existed before androgen deprivation therapy, followed by co-amplification of the AR gene and enhancer after the development of metastatic CRPC. The PDX of the primary tumour, without the AR amplification, was sensitive to AR-directed treatments, including castration, enzalutamide, and apalutamide. The PDX of the metastasis, with the AR amplification, had higher AR and AR-V7 expression in castrate conditions, and was resistant to castration, apalutamide, and enzalutamide in vivo. Treatment with a BET inhibitor outperformed the AR-directed therapies for the metastasis, resulting in tumour regression for some, but not all, grafts. Therefore, this study provides novel matched PDXs to test potential treatments that target the overabundance of AR in tumours with AR enhancer amplifications. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Topics: Androgen Antagonists; Androgens; Animals; Antineoplastic Agents; Benzamides; Disease Models, Animal; Disease Progression; Heterografts; Humans; Male; Mice; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins; Whole Genome Sequencing

The treatment of advanced prostate cancer has evolved due to recent advances in molecular research and new drug development. Dynamic aberrations in the androgen receptor, DNA repair genes, PTEN-PI3K, and other pathways drive the behavior of advanced prostate cancer allowing a better selection of therapies in each patient. Tumor testing for BRCA1 and BRCA2 is recommended for patients with metastatic prostate cancer, also considering a broad panel to guide decisions and genetic counseling. In symptomatic metastatic patients, castration should be stared to palliate symptoms and prolong survival. In high-risk or high-volume metastatic hormone-naïve patients, castration should be combined with docetaxel, abiraterone, enzalutamide or apalutamide. Radiotherapy to the primary tumor combined with systemic therapy is recommended in low-volume mHNPC patients. In patients with non-metastatic castration-resistant tumors, risk stratification can define the frequency of imaging. Adding enzalutamide, darolutamide or apalutamide to these patients prolongs metastasis-free and overall survival, but potential adverse events need to be taken into consideration. The choice of docetaxel, abiraterone or enzalutamide for treating metastatic castration-resistant patients depends on previous therapies, with cabazitaxel being also recommended after docetaxel. Olaparib is recommended in BRCA1/BRCA2 mutated castration-resistant patients after progression on at least one new hormonal therapy. Aggressive variants of prostate cancer respond to platinum-based chemotherapy. To optimize treatment efficiency, oncologists should incorporate all of these advances into an overall therapeutic strategy.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents; Benzamides; Combined Modality Therapy; Docetaxel; Genes, BRCA1; Genes, BRCA2; Genetic Testing; Humans; Male; Medical Oncology; Nitriles; Orchiectomy; Phenylthiohydantoin; Phthalazines; Piperazines; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radiotherapy; Randomized Controlled Trials as Topic; Societies, Medical; Spain; Thiohydantoins

Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR- neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN, TP53, and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR+ CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR+/NE+ double-positive "amphicrine" mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53, and the loss of RB1 but occurred via emergence of an AR-/NE- double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

Topics: Abiraterone Acetate; Animals; Antineoplastic Agents; Benzamides; Carcinoma, Neuroendocrine; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Enhancer of Zeste Homolog 2 Protein; Male; Mice; Neoplasm Transplantation; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Receptors, Androgen; Retinoblastoma Binding Proteins; SOXB1 Transcription Factors; Thiohydantoins; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Tubulin-β3 encoded by the Tubulin-β3 (TUBB3) gene is a microtubule protein. Previous studies have shown that TUBB3 expression is upregulated in castration-resistant prostate cancer (CaP) and is involved in taxane resistance. However, the biological mechanism of TUBB3 involvement in the progression to castration-resistant CaP is not fully elucidated. This study aimed to analyze the expression and function of TUBB3 in localized and metastatic CaP.. TUBB3 expression was determined using immunohistochemistry in localized and metastatic CaP. We also investigated the association between TUBB3, phosphatase and tensin homolog (PTEN), and neuroendocrine differentiation and examined the involvement of TUBB3 in new antiandrogen drugs (enzalutamide and apalutamide) resistance in metastatic CaP.. In 155 cases of localized CaP, immunohistochemistry showed that 5 (3.2%) of the CaP cases were positive for tubulin-β3. Kaplan-Meier analysis showed that high expression of tubulin-β3 was associated with poor prostate-specific antigen recurrence-free survival after radical prostatectomy. In 57 cases of metastatic CaP, immunohistochemistry showed that 14 (25%) cases were positive for tubulin-β3. Tubulin-β3 expression was higher in metastatic CaP than in localized CaP. High tubulin-β3 expression was correlated with negative PTEN expression. TUBB3 expression was increased in neuroendocrine CaP based on several public databases. PTEN knockout decreased the sensitivity to enzalutamide and apalutamide in 22Rv-1 cells. TUBB3 knockdown reversed the sensitivity to enzalutamide and apalutamide in PTEN-CRISPR 22Rv-1 cells. High expression of tubulin-β3 and negative expression of PTEN were significantly associated with poor overall survival in metastatic CaP treated with androgen deprivation therapy.. These results suggest that TUBB3 may be a useful predictive biomarker for survival and play an essential role in antiandrogen resistance in CaP.

Topics: Aged; Benzamides; Cell Differentiation; Humans; Male; Middle Aged; Neoplasm Metastasis; Neuroendocrine Tumors; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; PTEN Phosphohydrolase; Retrospective Studies; Thiohydantoins; Tubulin

Men who initially present with localized prostate cancer and later develop metachronous metastases have a better prognosis than men with de novo metastatic disease and often have a low burden of disease on conventional imaging. Some have disease amenable to metastasis-directed therapy for lymph node or bone metastases, a strategy used by some because no documented overall survival (OS) benefit of combination systemic therapy in this setting. We report data for patients prospectively classified as "M0" at initial diagnosis from the interim analysis of the ENZAMET trial, with 34 mo of median follow-up for survivors. A total of 312 (28%) of the 1125 enrolled patients were classified as M0 at diagnosis, and 205 (66%) of the 312 patients had low-volume disease at study entry as per the CHAARTED criteria. The hazard ratio for OS, that is, HR(OS), was 0.56 (95% confidence interval [CI]: 0.29-1.06) with the addition of enzalutamide for all patients with metachronous metastatic hormone-sensitive prostate cancer, and for the low-volume subset the HR(OS) was 0.40 (95% CI: 0.16-0.97). The 3-yr OS was 83% without and 89% with enzalutamide for all patients with metachronous metastases, and 83% and 92%, respectively, for the low-volume subset. Intensification of hormonal therapy should strongly be considered for these men. PATIENT SUMMARY: Many men present with prostate cancer that has spread to distant sites beyond the prostate gland years after their initial diagnosis and treatment, while others have distant spread at the time the cancer is diagnosed. On average, men whose cancer comes back years after the initial diagnosis often survive much longer than men whose cancer has been found to spread to distant sites when it is first diagnosed. In this report, we demonstrate strong evidence for the first time that the survival of men whose cancer comes back years later is improved when drugs such as enzalutamide or apalutamide are added to testosterone suppression in this setting.

Topics: Androgen Antagonists; Antineoplastic Agents; Benzamides; Clinical Trials as Topic; Humans; Male; Neoplasms, Second Primary; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Thiohydantoins

In the placebo-controlled SPARTAN study, apalutamide added to androgen-deprivation therapy (ADT) improved metastasis-free survival, second progression-free survival (PFS2), and overall survival (OS) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). Mechanisms of resistance to apalutamide in nmCRPC require evaluation.. In a subset of patients from SPARTAN, aberrations were assessed at baseline and end of study treatment (EOST) using targeted next-generation sequencing or qRT-PCR. Circulating-tumor DNA (ctDNA) levels were assessed qualitatively. Select aberrations in androgen receptor (AR) and other common PC-driving genes were detected and summarized by the treatment group; genomic aberrations were summarized in ctDNA-positive samples. Association between detection of aberrations in all patients and outcomes was assessed using Cox proportional-hazards models and multivariate analysis.. In 247 patients, the overall prevalence of ctDNA, AR aberrations, and. Apalutamide plus ADT did not increase detectable AR/non-AR aberrations over ADT alone. Detectable ctDNA, AR aberrations, and

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Biomarkers, Tumor; Disease Progression; Drug Therapy, Combination; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Risk Assessment; Survival Rate; Thiohydantoins

Apalutamide, a competitive inhibitor of the androgen receptor, is being increasingly used for the treatment of prostate cancer. There have been few reports of interstitial lung disease in clinical trials of apalutamide. However, two cases of apalutamide-induced interstitial lung disease with respiratory failure in Japanese males, who were successfully treated with high-dose corticosteroids, are presented here. These cases suggest that clinicians should be alert to the potentially life-threatening risk of pulmonary toxicity associated with apalutamide treatment.

Topics: Antineoplastic Agents; Humans; Japan; Lung Diseases, Interstitial; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Apalutamide is a next-generation androgen receptor inhibitor approved for treatment of subjects with high-risk, non-metastatic, castration-resistant prostate cancer (NM-CRPC).. The objective of this study was to characterize the population pharmacokinetics of apalutamide and its metabolite N-desmethyl-apalutamide in healthy male and castration-resistant prostate cancer subjects.. Plasma concentration data for apalutamide and N-desmethyl-apalutamide from 1092 subjects (seven clinical studies) receiving oral apalutamide (30-480 mg) once daily were pooled for a population pharmacokinetic analysis using a non-linear mixed-effect modelling approach. The impact of clinically relevant covariates was also assessed.. Apalutamide absorption was rapid, and the apparent steady-state volume of distribution was large (276 L), reflecting a wide body distribution. Apalutamide was eliminated slowly, with its apparent clearance increasing from 1.31 L/h after the first dose to 2.04 L/h at steady state. No evidence of time-dependent disposition was observed for N-desmethyl-apalutamide, which was also widely distributed and slowly cleared (1.5 L/h). After 4 weeks of treatment, more than 95% of steady-state exposure of apalutamide and N-desmethyl-apalutamide was reached. At a dose of apalutamide 240 mg/day, apalutamide and N-desmethyl-apalutamide exposure exhibited 5.3- and 85.2-fold accumulation in plasma, respectively. Inter-individual variability in apalutamide apparent clearance is low (< 20%). Among the covariates evaluated, apalutamide and N-desmethyl-apalutamide exposure were statistically associated only with health status, body weight, and albumin concentration, and the effect was low (< 25%).. A population pharmacokinetic modelling approach was successfully applied to describe the pharmacokinetics of apalutamide and N-desmethyl-apalutamide. No clinically relevant covariates were identified as predictors of apalutamide and N-desmethyl-apalutamide pharmacokinetics.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Androgen Receptor Antagonists; Biological Variation, Population; Body Weight; Case-Control Studies; Health Status; Healthy Volunteers; Humans; Male; Middle Aged; Models, Theoretical; Predictive Value of Tests; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Among various therapeutic options available for metastatic castration-resistant prostate cancer (mCRPC), only apalutamide and enzalutamide have shown evidences of improved metastasis-free survival (MFS) for non-metastatic castration-resistant prostate cancer (nmCRPC). However, there is a paucity of evidence to indicate who may be targeted for aggressive therapy among patients with nmCRPC. The objectives of this retrospective study were to explore predictors of metastasis in patients with nmCRPC and to identify a subpopulation of patients with nmCRPC who may benefit from aggressive therapy.. A total of 115 patients with CRPC who had no metastasis detected at the time of diagnosis of CRPC were included in this retrospective study. All patients were treated at Jikei University and its affiliated hospitals. The primary outcome measure was MFS from the time of diagnosis of CRPC. Predictors of MFS were also explored with a multivariate Cox hazard model.. The median observation period after diagnosis of CRPC was 30 months (range 2-143 months). Kaplan-Meier analysis revealed a median MFS of 76. Multivariate analysis demonstrated that low alkaline phosphatase (ALP) values at diagnosis of CRPC and favorable response to primary androgen deprivation therapy (ADT) were significant predictors of longer MFS (P = 0.011, and 0.031, respectively).. Results of this study suggest that high ALP values at diagnosis of CRPC and poor response to primary ADT may predict the propensity of metastasis in patients with nmCRPC. Further prospective studies will be required enrolling more patients to confirm our findings.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Androgen Antagonists; Benzamides; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Thiohydantoins; Treatment Outcome

Topics: Administration, Oral; Androstenes; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

The present study aimed to indirectly compare apalutamide and enzalutamide with respect to tolerability and health-related quality of life (HRQoL) among men with non-metastatic castration-resistant prostate cancer (nmCRPC).. Patient-level data from the SPARTAN study [apalutamide + androgen deprivation therapy (ADT) versus placebo + ADT] and aggregate published data from the PROSPER study (enzalutamide + ADT versus placebo + ADT) were used. Anchored matching-adjusted indirect comparison (MAIC) was conducted by weighting patients' baseline characteristics from SPARTAN to match aggregated baseline characteristics in PROSPER. Odds ratios (ORs) of reported adverse events (AEs) and baseline-to-follow-up least squares mean differences in HRQoL [measured with Functional Assessment of Cancer Therapy-Prostate (FACT-P) score] with 95% credible intervals were re-estimated for SPARTAN arms using weighted population and indirectly compared with those in PROSPER through a Bayesian framework. Events of special interest included fatigue, hot flush, nausea, diarrhea, hypertension, falls, dizziness, decreased appetite, arthralgia, asthenia and headache. In addition, any AEs and serious AEs were explored.. Of 1207 SPARTAN patients, 1171 were matched to 1401 PROSPER patients. Relative to enzalutamide, apalutamide demonstrated better tolerability as evidenced by the highest probability of reduced occurrence of fatigue [p(OR < 1) = 99.5%], hypertension [p(OR < 1) = 99.2%], decreased appetite [p(OR < 1) = 98.3%], fall [p(OR < 1) = 90.3%], headaches [p(OR < 1) = 86.7%], and nausea [p(OR < 1) = 80.0%]. The probabilities of reduced occurrence of any AEs and SAEs with apalutamide versus enzalutamide were 66.9% and 90.9%, respectively. Relative to enzalutamide, apalutamide treatment was associated with a higher probability of a better HRQoL based on the FACT-P total score [p(diff > 0) = 73.1%]. The probability of a better HRQoL with apalutamide versus enzalutamide was highest for the physical [p(diff > 0) = 97.3%] and functional [p(diff > 0) = 86.7%] wellbeing subscales, and the pain-related subscale [p(diff > 0) = 90.1%].. Anchored MAIC suggests that treatment of men with nmCRPC with apalutamide is associated with a higher probability of better tolerability due to fewer AEs and better HRQoL than enzalutamide.

Topics: Androgen Receptor Antagonists; Bayes Theorem; Benzamides; Disease-Free Survival; Humans; Male; Middle Aged; Nitriles; Pain; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins; Treatment Outcome

Metastasis-free survival (MFS) has been shown to be predictive of overall survival (OS) in hormone-sensitive localized prostate cancer. We evaluated the relationship between MFS and OS in nonmetastatic castration-resistant prostate cancer (nmCRPC).. A retrospective analysis of 1207 high-risk patients with nmCRPC from the SPARTAN study (clinicaltrials.gov, NCT01946204) was undertaken. Landmark analyses of MFS status at several time points from randomization were performed to minimize guarantee-time bias. Hazard ratio (HR) of death as a function of MFS status was estimated based on a Cox proportional hazards model with 2-sided 95% confidence interval (CI). Estimated HRs were adjusted for stratification factors. Correlation analysis was performed using the Fleischer method.. At all time points, MFS status strongly predicted OS. At landmark time points of 6, 9, and 12 months, risk of death was significantly higher for patients with metastases versus those without (adjusted HR at 6 months = 4.12; 95% CI, 2.60-6.54; P < .0001). MFS was positively correlated with OS based on the Fleischer method (HR, 0.69; 95% CI, 0.69-0.70; P < .0001). Approximately one-half of the variability in OS can be explained by MFS.. Metastasis development, regardless of time point, is associated with significantly greater risk of death in men with high-risk nmCRPC; hence, MFS is predictive of OS.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Clinical Trials, Phase III as Topic; Disease-Free Survival; Follow-Up Studies; Humans; Kallikreins; Male; Middle Aged; Proportional Hazards Models; Prostate; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Risk Factors; Thiohydantoins

Proxalutamide is a newly developed androgen receptor (AR) antagonist for the treatment of castration-resistant prostate cancer (PCa) that has entered phase III clinical trials. In the present study, we intended to elucidate the antitumor efficacy of proxalutamide through the metabolomic profiling of PCa cells. Two AR-positive PCa cell lines and two AR-negative PCa cell lines were investigated. Cell viability assays based on ATP quantitation were conducted. LC-Q/TOF-MS was used to analyze intracellular metabolites before or after the administration of proxalutamide and two other clinical AR antagonists (bicalutamide and enzalutamide). The results of this study showed that the inhibitory effect of proxalutamide on PCa cell proliferation was better than that of bicalutamide and enzalutamide, and proxalutamide preferentially affected AR-positive PCa cells over AR-negative cells. The metabolic composition of PCa cells changed significantly after proxalutamide administration, and these changes in response to proxalutamide were significantly different from those in the presence of the two other AR antagonists. In AR-positive cells, proxalutamide significantly decreased the intracellular levels of glutamine, glutamate, glutathione, cysteine, glycine, aspartate, uridine, cytidine and thymidine. However, the effects of the two other antagonists on these discriminant metabolites were ambiguous, and no changes in these metabolites were found in AR-negative cells. Our findings indicate that proxalutamide has inhibitory effects on glutamine metabolism, redox homeostasis and de novo pyrimidine synthesis in AR-positive PCa cells that enhance the cellular sensitivity to proxalutamide.

Topics: Amino Acids; Androgen Receptor Antagonists; Anilides; Benzamides; Cell Line, Tumor; Cell Survival; Glutathione; Humans; Male; Metabolome; Metabolomics; Nitriles; Nucleosides; Oxazoles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Tosyl Compounds

Topics: Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

The antiandrogen therapeutics apalutamide and darolutamide entered the clinic in 2018 and 2019, respectively, for the treatment of castration-resistant prostate cancer (CRPC). Increased expression of the enzyme aldo-keto reductase 1C3 (AKR1C3) is phenotypic of CRPC. The enzyme acts to circumvent castration by producing potent androgens that drive proliferation. Furthermore, AKR1C3 mediates chemotherapeutic resistance to the standard of care, enzalutamide, a structural analogue of apalutamide. Resistance develops in almost all CRPC patients within three months of beginning treatment. Herein, we report that both apalutamide and the structurally distinct darolutamide induce AKR1C3 expression in

Topics: Aldo-Keto Reductase Family 1 Member C3; Androgen Antagonists; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Discovery; Drug Resistance, Neoplasm; Drug Therapy, Combination; Enzyme Inhibitors; Gene Expression Regulation; Humans; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Substrate Specificity; Thiohydantoins

Topics: Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Since 2018, apalutamide, darolutamide, and enzalutamide have been approved for the treatment of men with non-metastatic castration-resistant prostate cancer (M0CRPC). These approvals were based on the results of three separate randomized, placebo-controlled, phase III trials: SPARTAN (apalutamide), ARAMIS (darolutamide) and PROSPER (enzalutamide). These trials included men with M0CRPC and a short PSA doubling time (≤10 months). Results demonstrated a longer metastasis-free survival with these agents when used in conjunction with androgen deprivation therapy (ADT), compared to ADT alone. Updated results of these trials presented in the 2020 annual meeting of American Society of Oncology (ASCO) showed significantly improved overall survival with these agents. Based on these results, apalutamide, darolutamide, and enzalutamide can now be considered the standard of care treatment options for the treatment of men with M0CRPC.

Topics: Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Survival Analysis; Thiohydantoins; Treatment Outcome

Novel androgen deprivation agents delay metastasis in non-metastatic, castration-resistant, prostate cancer (nmCRPC). The recent regulatory guidance: considerations for metastasis-free survival endpoint in clinical trials, opens new opportunities in cell biology, medicinal chemistry and advanced imaging. Past failures are the likely result of equating tumour shrinkage to efficacy, rather than inhibition of tumour spread. In the future, the selection of anti-metastasis drug candidates will probably be based on anti-migratory rather than anti-proliferative potential. Oligometastatic cancer coupled with advanced imaging can serve as a clinical proof-of-concept model.

Topics: Androgen Antagonists; Benzamides; Cell Movement; Cell Proliferation; Disease Progression; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Practice Guidelines as Topic; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Pyrazoles; Testosterone; Thiohydantoins; Tumor Burden; United States; United States Food and Drug Administration

Topics: Castration; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

To perform an adjusted indirect comparison of the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with a high risk of progression to metastatic disease.. After carrying out a literature search, we performed an adjusted indirect comparison (Bucher et al.) of the relative efficacy of enzalutamide and apalutamide in patients with nmCRPC with a high risk of progression to metastatic disease. The outcomes included were metastasis-free survival (MFS) and PSA response rate (PSARR).. There were no statistically significant differences between enzalutamide and apalutamide regarding the analysed outcomes. For the comparison enzalutamide+ADT vs. apalutamide+ADT: MFS a HR (95% CI)=1,036 (0.781-1.373) was obtained. For PSARR, a RR (95% CI)=0.81 (0.339-1.938) was obtained.. The adjusted indirect comparison performed in this study shows that there are no statistically significant differences in terms of efficacy regarding MFS and PSARR between enzalutamide+ADT and apalutamide+ADT in patients with nmCRPC with a high risk of progression to metastatic disease. However, in order to confirm these results, an independent trial with direct comparison between both drugs would be required.

Topics: Aged; Benzamides; Disease Progression; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Risk Assessment; Thiohydantoins; Treatment Outcome

Topics: Antineoplastic Agents, Hormonal; Benzamides; Bone Diseases; Cardiovascular Diseases; Humans; Male; Mental Disorders; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Topics: Castration; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Humans; Male; Neoplasm Metastasis; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Randomized Controlled Trials as Topic; Thiohydantoins; Treatment Outcome

Topics: Antineoplastic Agents; Drug Approval; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; United States; United States Food and Drug Administration

Topics: Antineoplastic Agents; Disease-Free Survival; Drug Approval; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; United States; United States Food and Drug Administration

Topics: Androgen Antagonists; Humans; Male; Neoplasm Recurrence, Local; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Thiohydantoins

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have historically had few treatment options. Recently, randomized controlled trials have examined the benefit of apalutamide and enzalutamide in these patients. We sought to perform an indirect treatment comparison using a network meta-analysis approach to compare the relative efficacy and toxicity of these two agents. The primary outcome of this analysis was metastasis-free survival (MFS) while secondary outcomes were time to prostate-specific antigen progression, overall survival, and adverse events. The Bucher technique for indirect comparison was used to compare apalutamide and enzalutamide using the common placebo comparator. We found no evidence of a significant difference in MFS (hazard ratio 1.04, 95% confidence interval 0.78-1.37) between enzalutamide and apalutamide. Similarly, there were no differences for any of the secondary outcomes. While indirect comparisons cannot supplant direct comparative data, this analysis suggests that apalutamide and enzalutamide are similarly effective in delaying metastases for patients with nmCRPC. PATIENT SUMMARY: Historically, there have been few treatment options for prostate cancer patients receiving androgen deprivation therapy who have rising prostate-specific antigen levels without obvious recurrence of cancer. Recent randomized controlled trials demonstrated that treatment with enzalutamide and apalutamide delayed the development of metastatic cancer. This study demonstrates through an indirect comparison that both medications are likely to have similar efficacy and side-effect profiles.

Topics: Androgen Antagonists; Benzamides; Disease Progression; Disease-Free Survival; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Thiohydantoins; Treatment Outcome

Androgen receptor (AR) mutations arise in patients developing resistance to hormone deprivation therapies. Here we describe BAY 1024767, a thiohydantoin derivative with strong antagonistic activity against nine AR variants with mutations located in the AR ligand-binding domain (LBD), and against wild-type AR. Antagonism was maintained, though reduced, at increased androgen levels. Anti-tumor efficacy was evidenced in vivo in the KuCaP-1 prostate cancer model which bears the W741C bicalutamide resistance mutation and in the syngeneic prostate cancer rat model Dunning R3327-G. The prevalence of six selected AR mutations was determined in plasma DNA originating from 100 resistant patients and found to be at least 12%. Altogether the results show BAY 1024767 to be a strong antagonist for several AR mutants linked to therapy resistance, which opens the door for next-generation compounds that can benefit patients based on their mutation profile.

Topics: Androgen Receptor Antagonists; Animals; Caco-2 Cells; Cell Line, Tumor; Chlorocebus aethiops; COS Cells; Down-Regulation; Humans; Male; Mice; Mice, SCID; Mutation; Prostatic Neoplasms, Castration-Resistant; Random Allocation; Rats; Receptors, Androgen; Thiohydantoins; Transfection; Xenograft Model Antitumor Assays

Resistance of prostate cancer to castration is currently an unavoidable problem. The major mechanisms underlying such resistance are androgen receptor (AR) overexpression, androgen-independent activation of AR, and AR mutation. To address this problem, we developed an AR pure antagonist, CH5137291, with AR nuclear translocation-inhibiting activity, and compared its activity and characteristics with that of bicalutamide. Cell lines corresponding to the mechanisms of castration resistance were used: LNCaP-BC2 having AR overexpression and LNCaP-CS10 having androgen-independent AR activation. VCaP and LNCaP were used as hormone-sensitive prostate cancer cells. In vitro functional assay clearly showed that CH5137291 inhibited the nuclear translocation of wild-type ARs as well as W741C- and T877A-mutant ARs. In addition, it acted as a pure antagonist on the transcriptional activity of these types of ARs. In contrast, bicalutamide did not inhibit the nuclear translocation of these ARs, and showed a partial/full agonistic effect on the transcriptional activity. CH5137291 inhibited cell growth more strongly than bicalutamide in VCaP and LNCaP cells as well as in LNCaP-BC2 and LNCaP-CS10 cells in vitro. In xenograft models, CH5137291 strongly inhibited the tumor growth of LNCaP, LNCaP-BC2, and LNCaP-CS10, whereas bicalutamide showed a weaker effect in LNCaP and almost no effect in LNCaP-BC2 and LNCaP-CS10 xenografts. Levels of prostate-specific antigen (PSA) in plasma correlated well with the antitumor effect of both agents. CH5137291 inhibited the growth of LNCaP tumors that had become resistant to bicalutamide treatment. A docking model suggested that CH5137291 intensively collided with the M895 residue of helix 12, and therefore strongly inhibited the folding of helix 12, a cause of AR agonist activity, in wild-type and W741C-mutant ARs. In cynomolgus monkeys, the serum concentration of CH5137291 increased dose-dependently and PSA level decreased 80% at 100 mg/kg. CH5137291 is expected to offer a novel therapeutic approach against major types of castration-resistant prostate cancers.

Topics: Anilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Humans; Male; Mice; Molecular Docking Simulation; Mutation; Nitriles; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Transport; Receptors, Androgen; Sulfonamides; Thiohydantoins; Tosyl Compounds; Xenograft Model Antitumor Assays

Despite the impressive clinical activity of the second-generation antiandrogens enzalutamide and ARN-509 in patients with prostate cancer, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity due to a missense mutation (F876L) in the ligand-binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of castration-resistant prostate cancer (CRPC). Importantly, the AR F876L mutant is detected in plasma DNA from ARN-509-treated patients with progressive CRPC. Thus, selective outgrowth of AR F876L is a clinically relevant mechanism of second-generation antiandrogen resistance that can potentially be targeted with next-generation antiandrogens.. A missense mutation in the ligand-binding domain of the androgen receptor F876L confers resistance to the second-generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARN-509-treated patients with progressive disease. These results chart a new path for the discovery and development of next-generation antiandrogens that could be coupled with a blood-based companion diagnostic to guide treatment decisions.

Topics: Androgen Antagonists; Benzamides; Cell Line, Tumor; DNA; Drug Resistance, Neoplasm; Humans; Male; Molecular Targeted Therapy; Mutation, Missense; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins

The appearance of a mutant androgen receptor, AR(F876L), in prostate cancer cells chronically exposed to enzalutamide or ARN-509 promotes a switch from antagonist to agonist receptor function, undermining the potential long-term effectiveness of these second-generation antiandrogen drugs.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Thiohydantoins