thiohydantoins and abiraterone

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

Prostate cancer (PC) is a major health issue in developed countries, with, on the one hand, men suffering from sequelae related to unnecessary treatment of non-lethal PC, and, on the other hand, still dying because of advanced PC that progresses to castration-resistant disease. Systemic treatment is the mainstay of therapy of castration-resistant PC (CRPC). To date, a multitude of systemic agents have been tested and many of these have failed to provide a clinically meaningful benefit in CRPC, while others have been approved by the US Food and Drug Administration and/or the European Medicines Agency, including antiandrogen hormonal drugs (abiraterone, enzalutamide, apalutamide), chemotherapy (docetaxel and cabazitaxel), immunotherapy (Sipuleucel-T), and radiopharmaceutical (Radium-223) agents. In this review, systemic treatments regarded as most likely to have an impact in clinical practice are presented and discussed. In addition to the pivotal clinical studies, selected retrospective and non-randomized clinical trials are also discussed if deemed to have an impact on clinical practice or future research. A comprehensive appraisal of the expanding landscape of systemic therapies for advanced PC is provided from an expert perspective, with a focus on novel classification and diagnostic tools that have been paving the way for the development of precision medicine in PC.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Clinical Trials as Topic; Docetaxel; Humans; Immunotherapy; Male; Molecular Targeted Therapy; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Radiopharmaceuticals; Radium; Retrospective Studies; Taxoids; Thiohydantoins; Tissue Extracts

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

The review examines recent advances in second-line hormonal therapy for the treatment of castrate-resistant prostate cancer (CRPC).. Recent data highlight the continued importance of androgen signaling in CRPC. These findings have spurred the development of novel inhibitors of adrenal and intra-tumoral androgen synthesis and novel androgen signaling inhibitors with activity in CRPC. In the past year abiraterone acetate, a CYP17 (17α-hydroxylase/17, 20 lyase) inhibitor, received US FDA approval for use in the treatment of metastatic CRPC in patients previously treated with docetaxel. Additionally, the novel androgen signaling inhibitor MDV3100 has been reported to confer a survival advantage compared to placebo in the same patient population. Here we review the scientific rationale for targeting androgen signaling in CRPC and the recent pivotal trials that support the use of novel second-line hormonal therapies. Additionally, we summarize ongoing preclinical and clinical efforts to ascertain and overcome mechanisms of resistance.. Novel inhibitors of extra-gonadal androgen synthesis and androgen receptor function demonstrate the continued importance of androgen signaling in CRPC. These agents have improved clinical outcomes for patients with metastatic CRPC.

Topics: Androgen Antagonists; Androgens; Androstadienes; Androstenes; Androstenols; Antineoplastic Agents; Benzamides; Benzimidazoles; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Male; Neoplasms, Hormone-Dependent; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Steroid 17-alpha-Hydroxylase; Thiohydantoins

Recent results of phase III randomized studies confirm that targeting the androgen receptor (AR)-through inhibition of androgen synthesis or through AR targeting directly-can improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC), a condition previously considered to be "refractory" to further hormonal manipulation. These data validate in the clinical setting much of the scientific work of the previous decade that has demonstrated the extent of and mechanisms behind retained AR signaling in advanced prostate cancer. The convergence of these observations effectively changes the perspective with which androgen deprivation is utilized in prostate cancer, and forms the basis for further expansion of systemic therapy in the disease. In this review, the rationale for and clinical results with these new therapies will be discussed as will the future directions required to fully leverage these therapeutic modalities to the maximum clinical benefit for patients.

Topics: Androgen Receptor Antagonists; Androstenes; Androstenols; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Benzamides; Docetaxel; Drug Resistance, Neoplasm; Humans; Ketoconazole; Male; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Taxoids; 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

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

Docetaxel represent the standard of care in patients with metastatic, hormone sensitive prostate cancer. However, androgen receptor axis targeted therapies have also been shown to be effective. We aimed to analyze findings in randomized controlled trials investigating first-line treatment for hormone sensitive prostate cancer.. We systematically reviewed the literature according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and the PICO (Population, Intervention, Comparator, Outcomes) methodology. Outcomes of interest were overall and progression-free survival, and the rate of high grade adverse events.. No treatment was superior to docetaxel in terms of overall survival. However, abiraterone (HR 0.89, 95% CI 0.76-1.05), enzalutamide (HR 0.90, 95% CI 0.69-1.19) and apalutamide (HR 0.90, 95% CI 0.67-1.22) showed nonstatistically significant lower overall mortality rates than docetaxel. Abiraterone (HR 0.71, 95% CI 0.59-0.86), enzalutamide (HR 0.61, 95% CI 0.49-0.75) and apalutamide (HR 0.74, 95% CI 0.57-0.95) also showed statistically significant lower disease progression rates than docetaxel. Furthermore, abiraterone (OR 0.83, 95% CI 0.56-1.21) showed no statistically significant lower rate of high grade adverse events compared to docetaxel. Finally, enzalutamide (OR 0.56, 95% CI 0.35-0.92) and apalutamide (OR 0.44, 95% CI 0.24-0.79) showed statistically significant lower rates of high grade adverse events compared to docetaxel.. Treatment with androgen receptor axis targeted therapies combined with androgen deprivation therapy in patients with hormone sensitive prostate cancer did not offer a statistically significant advantage in overall survival compared to the standard, docetaxel. However, it was associated with a lower disease progression rate. Moreover, apalutamide and enzalutamide offer a better safety profile.

Topics: Androgen Antagonists; Androstenes; Antineoplastic Agents; Benzamides; Disease Progression; Docetaxel; Humans; Male; Network Meta-Analysis; Nitriles; Phenylthiohydantoin; Progression-Free Survival; Prostatic Neoplasms; Randomized Controlled Trials as Topic; Standard of Care; Thiohydantoins

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