taxane and Prostatic-Neoplasms--Castration-Resistant

Radioligand therapy (RLT) with

Topics: Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Taxanes have been used as monotherapy for metastatic prostate cancer for two decades.. The current status of docetaxel and cabazitaxel in the treatment sequence for metastatic prostate cancer needs to be clarified.. Overview of the existing literature regarding approval, dosage and new combination options for metastatic castration-resistant prostate cancer (mCRPC).. Taxanes represent one, but no longer the only treatment option for mCRPC. Previously, monotherapy was standard of care in the first and second line for mCRPC; nowadays taxanes are thrusted in the background due to new encouraging drug options. Based on the promising data of docetaxel in triple therapy setting for hormone-sensitive stage, its role as monotherapy in mCRPC needs to be clarified. Cabazitaxel is an alternative to PSMA radioligand therapy after failure of novel hormonal therapy (NHT) and docetaxel. Therapy adherence for taxanes can be significantly improved by dosage adjustments. Both treatment-related neuroendocrine prostate cancer (t-NEPC) and aggressive variant of prostate cancer (AVPC) represent a challenge for experienced uro-oncologists. Here, the combination of taxane plus platinum represents a promising option.. Taxanes are indicated in different stages of metastatic prostate cancer. Their use, particularly in combination with other drugs, appears to be promising. Traditional sequential taxane monotherapy regimens will be challenged by novel systemic therapy approaches.. HINTERGRUND: Seit 2 Jahrzehnten werden Taxane in der Monotherapie des metastasierten Prostatakarzinoms eingesetzt.. Es gilt den Stellenwert von Docetaxel und Cabazitaxel in der Therapiesequenz des metastasierten Prostatakarzinoms zu klären.. Der Beitrag gibt eine Übersicht der vorhandenen Literatur bezüglich Zulassung, Dosierung und neuer Therapieoptionen beim metastasierten kastrationsresistenten Prostatakarzinom (mCRPC).. Taxane stellen eine, aber nicht mehr DIE Therapieoption beim mCRPC dar. Vormals DER Standard als Monotherapie in der Erst- und Zweitlinie bei mCRPC, stehen Taxane aufgrund neuer vielversprechender Medikamentenoptionen nicht mehr im primären Vordergrund. Aufgrund der Einsatzmöglichkeit von Docetaxel im hormonsensitiven Stadium gilt es, seinen sinnvollen Einsatz als Monotherapie beim mCRPC zu klären. Cabazitaxel ist eine Alternative zur PSMA-Radioligandentherapie („prostate-specific membrane antigen“) nach Versagen von NHT (neue hormonelle Therapie) und Docetaxel. Durch Anpassung der Medikamentendosis an die Komorbiditäten des mCRPC-Patienten kann die Therapieakzeptanz deutlich verbessert werden. Sowohl das behandlungsinduzierte neuroendokrine Prostatakarzinom (t-NEPC) als auch die aggressiven Prostatakarzinomvarianten (AVPC) stellen eine Herausforderung für erfahrene Uroonkolog*innen dar. Hier ist die Kombination aus Taxan plus Platinderivat eine vielversprechende Option.. Taxane haben ihre Indikation in verschiedenen Stadien des metastasierten Prostatakarzinoms. Ihr Einsatz insbesondere in Kombination mit anderen Substanzklassen erscheint vielversprechend. Traditionelle sequenzielle Monotherapieschemata der Taxane müssen durch neuartige Systemtherapieansätze hinterfragt werden.

Topics: Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Taxoids

Extensive experience outside the United States as well as randomized phase II and phase III data demonstrate that. This review discusses the development and studies leading to the approval of

Topics: Clinical Trials, Phase II as Topic; Dipeptides; Humans; Lutetium; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Radiopharmaceuticals; Randomized Controlled Trials as Topic; Taxoids; Treatment Outcome

Many therapeutic options are now available for men with metastatic castration-resistant prostate cancer (mCRPC), including next-generation androgen receptor axis-targeted therapies (AATTs), immunotherapy, chemotherapy, and radioisotope therapies. No clear consensus has been reached for the optimal sequencing of treatments for patients with mCRPC, and few well-validated molecular markers exist to guide the treatment decisions for individual patients. The androgen receptor splice variant 7 (AR-V7), a splice variant of the androgen receptor mRNA resulting in the truncation of the ligand-binding domain, has emerged as a biomarker for resistance to AATT. AR-V7 expression in circulating tumor cells has been associated with poor outcomes in patients treated with second- and third-line AATTs. Clinically validated assays are now commercially available for the AR-V7 biomarker. In the present review of the current literature, we have summarized the biology of resistance to AATT, with a focus on the AR-V7; and the clinical studies that have validated AR-V7 expression as a strong independent predictor of a lack of clinical benefit from AATTs. Existing evidence has indicated that patients with AR-V7-positive mCRPC will have better outcomes if treated with taxane chemotherapy regimens rather than additional AATTs.

Topics: Androgen Antagonists; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Male; Progression-Free Survival; Prostatic Neoplasms, Castration-Resistant; Protein Domains; Protein Isoforms; Receptors, Androgen; Taxoids

Multiple single-agent therapies improving survival are approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC), including two chemotherapies, two androgen-signaling axis-targeting agents, an immunotherapeutic vaccine, and a radiopharmaceutical. Combination therapy can target multiple oncogenic pathways simultaneously, while potentially curbing the development of treatment resistance.. To provide a succinct overview of taxane-based combination therapies currently being evaluated for the treatment of metastatic prostate cancer.. We searched MEDLINE/PubMed. Single-agent therapy yields modest increments in survival. The success of combining docetaxel with androgen deprivation to improve overall survival (OS) for metastatic hormone-sensitive disease suggests the potential of similar approaches in mCRPC. Several classes of biological drugs have previously been combined with docetaxel for mCRPC in clinical trials without improvement in OS. However, combining docetaxel or cabazitaxel with newer agents with established single-agent benefit, such as radium-223, second-generation androgen pathway-targeted agents, or other chemotherapies, has the potential to benefit patients when compared with taxane chemotherapy alone. Our search revealed that the majority of trials currently assessing taxanes are focused on combination therapies: a combination approach is being evaluated in 37 of 47 trials assessing docetaxel and in 18 of 34 trials assessing cabazitaxel.. Despite prior failures, novel taxane-based combination therapies have the potential to improve outcomes in mCRPC. Challenges include the absence of validated predictive biomarkers for the selection of suitable patients and the potential for enhanced toxicity.. Patients with metastatic prostate cancer have access to multiple therapies improving survival. Many advanced epithelial cancers are treated with combinations of drugs; however, prostate cancer has remained an exception. A number of clinical studies have shown that combining chemotherapy with other classes of therapy may improve patient outcomes in prostate cancer. Here, we summarize the various combinations that are tested in the clinic and review the results.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Humans; Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

androgen receptor variant 7 (AR-V7) has been suggested as potential marker for treatment selection in men with metastatic castration-resistant prostate cancer (mCRPC). The aim of the present review is to critically analyze: frequency of the AR-V7 expression in mCRPC cases-impact of AR-V7 expression on abiraterone, enzalutamide, and taxane therapy.. we searched in the Medline and Cochrane Library database from the literature of the past 10 years. We critically evaluated the level of evidence according to the European Association of Urology (EAU) guidelines.. 12 clinical trials were selected. The determination of AR-V7 in peripheral blood using circulating tumor cells mRNA seems to be the preferred method. At baseline, the mean percentage of cases with AR-V7 positivity was 18.3% (range 17.8%-28.8%). All data on mCRPC submitted to enzalutamide or abiraterone reported a significantly (P <.05) lower clinical progression-free survival (CPFS) and overall survival (OS) in AR-V7+ than AR-V7- cases (CPFS hazard ratio [HR]: 2.3; 95% CI 1.1-4.9; OS HR: 3.0; 95% CI 1.4-6.3). In mCRPC cases submitted to chemotherapies data are not homogeneous and some studies showed no association between CPFS or OS and AR-V7 status (OS HR 1.6; 95% CI 0.6-4.4; P = .40).. the suggestion is that taxane therapy is more efficacious than abiraterone or enzalutamide for men with AR-V7+ CRPC. On the contrary, clinical outcomes did not seem to differ significantly on the basis of the type of therapy used among AR-V7- cases.

Topics: Androstenes; Antineoplastic Agents; Benzamides; Biomarkers, Tumor; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Genetic Variation; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids

Despite the significant survival benefit of taxane therapy in metastatic castration-resistant prostate cancer (mCRPC), all patients inevitably develop treatment resistance. An understanding of resistance mechanisms has led to new therapies for prostate cancer (cabazitaxel, abiraterone and enzalutamide), all of which have improved survival following first-line docetaxel. Another treatment, currently in development, targets the prosurvival molecule clusterin. Custirsen, an antisense molecule that inhibits clusterin production, has shown promise in combination with docetaxel in mCRPC patients at risk for poor outcomes. Although optimal sequence and combination of available therapies is unclear, the heterogeneity of mCRPC suggests a continuing need for personalized treatment regimens and improved abilities to predict which patients will respond to the available treatment options.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Inflammation; Male; Microtubules; Molecular Chaperones; Neoplasm Metastasis; Patient Selection; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Taxoids; Treatment Outcome

The androgen receptor (AR) plays a key role in progression to metastatic castration-resistant prostate cancer (mCRPC). Despite the recent progress in targeting persistent AR activity with the next-generation hormonal therapies (abiraterone acetate and enzalutamide), resistance to these agents limits therapeutic efficacy for many patients. Several explanations for response and/or resistance to abiraterone acetate and enzalutamide are emerging, but growing interest is focusing on importance of AR splice variants (AR-Vs) and in particular of AR-V7. Increasing evidences highlight the concept that variant expression could be used as a potential predictive biomarker and a therapeutic target in advanced prostate cancer. Therefore, understanding the mechanisms of treatment resistance or sensitivity can help to achieve a more effective management of mCRPC, increasing clinical outcomes and representing a promising and engaging area of prostate cancer research.

Topics: Abiraterone Acetate; Alternative Splicing; Antineoplastic Agents; Benzamides; Bridged-Ring Compounds; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Staging; Nitriles; Patient Selection; Phenylthiohydantoin; Predictive Value of Tests; Prognosis; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

Until 2010 docetaxel was the only agent with a proven survival benefit in the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC is caused by augmented androgen/androgen receptor (AR) signaling involving AR hypersensitivity, promiscuous activation of the AR, de novo production of androgens and activation of the AR by cytokines and growth factors; these findings have led to the development of novel agents targeting AR signaling. Several novel drugs targeting the AR axis, including the cytochrome P17 inhibitor abiraterone acetate and anti-androgen enzalutamide (MDV3100), have shown promising results in prolonging survival in clinical trials in a postchemotherapy setting. Because of these encouraging findings, these drugs have also been evaluated in a pre-chemotherapy setting. In addition, several novel drugs targeting non-AR signaling, including the novel taxoid compound cabazitaxel, antisense oligonucleotide OGX-011 (custirsen), sipuleucel-T immunotherapy and Alpharadin-based radiotherapy, have also been demonstrated to improve overall survival in CRPC. However, there is no consensus with regard to the sequence in which these novel drugs and taxanes should be used in the treatment of CRPC. In this review, we summarize recently developed and developing novel agents for use against CRPC. We also discuss the sequence of use of these agents and taxanes, mainly from the standpoint of factors related to drug resistance.

Topics: Androgen Receptor Antagonists; Animals; Bridged-Ring Compounds; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Taxoids

To assess the efficacy and safety of darolutamide maintenance after successful taxane chemotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC).. Swiss Group for Clinical Cancer Research (SAKK) 08/16 is a randomized phase II study. Patients with mCRPC who received prior androgen-receptor pathway inhibitors (ARPIs) and subsequently had nonprogressive disease on a taxane were randomly assigned to darolutamide 600 mg twice a day or placebo twice a day. The primary end point was radiographic progression-free survival (rPFS) at 12 weeks. Secondary end points were rPFS, event-free survival, overall survival (OS), prostate-specific antigen (PSA) 50% response rate, and adverse events.. Overall, 92 patients were recruited by 26 centers. Prior taxane was docetaxel in 93% and cabazitaxel in 7%. Prior ARPI was abiraterone in 60%, enzalutamide in 31%, and both in 9%. rPFS at 12 weeks was significantly improved with darolutamide (64.7%. SAKK 08/16 met its primary end point, showing that switch maintenance with darolutamide after prior taxane chemotherapy and at least one ARPI resulted in a statistically significant but clinically modest rPFS prolongation with good tolerability. The median OS with darolutamide maintenance appears promising. Should these findings be confirmed in a larger trial, maintenance treatment could be a novel strategy in managing patients with mCRPC, especially those who responded well to prior ARPI.

Topics: Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Humans; Male; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

In VISION, the prostate-specific membrane antigen (PSMA)-targeted radioligand therapy lutetium-177 [. This multicentre, open-label, randomised, phase 3 trial was conducted at 84 cancer centres in nine countries in North America and Europe. Eligible patients were aged 18 years or older; had progressive PSMA-positive metastatic castration-resistant prostate cancer; an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2; and had previously received of at least one androgen receptor pathway inhibitor and one or two taxane-containing regimens. Patients were randomly assigned (2:1) to receive either [. Between June 4, 2018, and Oct 23, 2019, 831 patients were enrolled, of whom 581 were randomly assigned to the [. [. Advanced Accelerator Applications (Novartis).

Topics: Aged; Androgen Receptor Antagonists; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Pain; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Receptors, Androgen; Standard of Care; Taxoids

We previously reported that olaparib led to significantly longer imaging-based progression-free survival than the physician's choice of enzalutamide or abiraterone among men with metastatic castration-resistant prostate cancer who had qualifying alterations in homologous recombination repair genes and whose disease had progressed during previous treatment with a next-generation hormonal agent. The results of the final analysis of overall survival have not yet been reported.. In an open-label, phase 3 trial, we randomly assigned patients in a 2:1 ratio to receive olaparib (256 patients) or the physician's choice of enzalutamide or abiraterone plus prednisone as the control therapy (131 patients). Cohort A included 245 patients with at least one alteration in. The median duration of overall survival in cohort A was 19.1 months with olaparib and 14.7 months with control therapy (hazard ratio for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P = 0.02). In cohort B, the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. In the overall population (cohorts A and B), the corresponding durations were 17.3 months and 14.0 months. Overall, 86 of 131 patients (66%) in the control group crossed over to receive olaparib (56 of 83 patients [67%] in cohort A). A sensitivity analysis that adjusted for crossover to olaparib showed hazard ratios for death of 0.42 (95% CI, 0.19 to 0.91) in cohort A, 0.83 (95% CI, 0.11 to 5.98) in cohort B, and 0.55 (95% CI, 0.29 to 1.06) in the overall population.. Among men with metastatic castration-resistant prostate cancer who had tumors with at least one alteration in

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; Bridged-Ring Compounds; Cyclin-Dependent Kinases; Genes, BRCA1; Humans; Male; Middle Aged; Mutation; Neoplasm Metastasis; Phthalazines; Piperazines; Prostatic Neoplasms, Castration-Resistant; Survival Analysis; Taxoids

AEZS-108, formerly AN-152, is a cytotoxic hybrid molecule consisting of a luteinizing hormone-releasing hormone (LHRH) agonist moiety covalently coupled to doxorubicin, allowing it to deliver doxorubicin selectively to cells expressing LHRH receptors. LHRH receptors are expressed on the cell membrane of many tumors, including prostate cancer. This phase I study determined the maximum tolerated dose (MTD) of AEZS-108 in men with taxane- and castration-resistant prostate cancer (CRPC) while providing additional information on the safety profile and efficacy of this agent.. AEZS-108 was administered as an intravenous infusion every 21 days until progression or unacceptable toxicity in cohorts of 3 or 6 patients until the MTD was reached. Blood was collected for capture of circulating tumor cells (CTC) to visualize internalization of AEZS-108, an autofluorescent molecule.. The MTD of AEZS-108 in this cohort was 210 mg/m(2), which was lower than that seen in a phase I study conducted in women with endometrial or ovarian cancers. The dose-limiting toxicity was persistent neutropenia. Three patients had a PSA response with an additional 10 patients maintaining PSA stable disease. Of the 10 patients evaluable by RECIST criteria, 9 achieved stable disease. AEZS-108 internalization in CTCs was routinely visualized using its autofluorescence.. These findings show that AEZS-108 has an acceptable safety profile and a signal of efficacy, lowering PSA in heavily pretreated patients with prostate cancer, and that internalization of AEZS-108 in prostate cancer CTCs may be a viable pharmacodynamic marker. A phase II study in men with prostate cancer is ongoing.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Hormonal; Bridged-Ring Compounds; Doxorubicin; Drug Resistance, Neoplasm; Gonadotropin-Releasing Hormone; Humans; Male; Middle Aged; Neoplasm Grading; Neoplasm, Residual; Prostatic Neoplasms, Castration-Resistant; Retreatment; Taxoids; Treatment Outcome

Although new androgen-targeted therapies offer prolonged survival in metastatic castration-resistant prostate cancer (CRPC), most men still face progressive disease and require additional therapy. Oxaliplatin and pemetrexed have each shown modest activity in the treatment of CRPC. Given their favorable nonoverlapping toxicity profiles, we studied them in combination.. Men with CRPC whose disease had progressed on 1 or 2 previous chemotherapy regimens, including a taxane, were eligible. All participants received oxaliplatin 120 mg/m(2) and pemetrexed 500 mg/m(2) intravenously every 21 days. The primary end point was response rate; objective responses were determined using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, criteria and the Prostate Cancer Working Group (1999) criteria. Secondary end points included progression-free survival and OS.. Forty-seven men received a median of 6 cycles (range, 1-21). The overall response rate was 30% (95% confidence interval [CI], 18%-45%), including 10 men with RECIST responses of the 40 who had measurable disease (25%). Overall, 64% had a prostate-specific antigen (PSA) decline and 74% of men had clinical disease control (partial response or stable disease as their best response). Median progression-free survival was 5.8 months (95% CI, 3.8-7.6), with a median OS of 11.9 months. Six of 15 evaluable patients (40%) experienced a pain response. Nineteen patients (40%) experienced a grade 3 or 4 hematologic toxicity, and 16 (34%) experienced a grade 3 nonhematologic toxicity. One patient died while participating in the study.. Combination oxaliplatin and pemetrexed (PemOx) is an effective and tolerable second- or third-line treatment for men with CRPC.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Disease-Free Survival; Glutamates; Guanine; Humans; Male; Organoplatinum Compounds; Oxaliplatin; Pain; Pain Management; Pemetrexed; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Survival; Taxoids; Treatment Outcome

PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions.. mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy.. Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35).. Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

Topics: Ataxia Telangiectasia Mutated Proteins; BRCA2 Protein; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

There is limited real-world evidence on how increasing use of treatment intensification in metastatic castration-sensitive prostate cancer (mCSPC) has influenced treatment decisions in metastatic castration-resistant prostate cancer (mCRPC). The study objective was to evaluate the impact of novel hormonal therapy (NHT) and docetaxel use in mCSPC on first-line treatment patterns among patients with mCRPC in 5 European countries and the United States (US).. Physician-reported data on patients with mCRPC from the Adelphi Prostate Cancer Disease Specific Program were descriptively analyzed.. A total of 215 physicians provided data on 722 patients with mCRPC. Across 5 European countries and the US, 65% and 75% of patients, respectively, received NHT, and 28% and 9% of patients, respectively, received taxane chemotherapy as first-line mCRPC treatment. In Europe, patients who had received NHT in mCSPC (n = 76) mostly received taxane chemotherapy in mCRPC (55%). Patients who had received taxane chemotherapy, or who did not receive taxane chemotherapy or NHT in mCSPC (n = 98 and 434, respectively) mostly received NHT in mCRPC (62% and 73%, respectively). In the US, patients who had received NHT, taxane chemotherapy, or neither in mCSPC (n = 32, 12, and 72, respectively) mostly received NHT in mCRPC (53%, 83%, and 83%, respectively). Two patients in Europe were rechallenged with the same NHT.. These findings suggest that physicians consider mCSPC treatment history when making first-line treatment decisions in mCRPC. Further studies are needed to better understand optimal treatment sequencing, especially as new treatments emerge.

Topics: Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Treatment Outcome

Androgen receptor (AR) gene alterations, as detected by circulating tumor cell-free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration-resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real-world patient population of mCRPC experiencing disease progression on an ARPI.. In this IRB-approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild-type (AR. In this real-world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane-based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.

Topics: Androgen Receptor Antagonists; Biomarkers, Tumor; Cell-Free Nucleic Acids; Disease Progression; Genomics; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Taxoids

Androgen ablation therapy is the standard of care for newly diagnosed prostate cancer (PC) patients. PC that relapsed after hormonal therapy, referred to as castration-resistant PC (CRPC), often presents with metastasis (mCRPC) and is the major cause of disease lethality. The few available therapies for mCRPC include the Taxanes Docetaxel (DTX) and Cabazitaxel (CBZ). Alas, clinical success of Taxanes in mCRPC is limited by high intrinsic and acquired resistance. Therefore, it remains essential to develop rationally designed treatments for managing therapy-resistant mCRPC disease. The major effect of Taxanes on microtubule hyper-polymerization is a prolonged mitotic block due to activation of the Spindle Assembly Checkpoint (SAC). Taxane-sensitive cells eventually inactivate SAC and exit mitosis by mitotic catastrophe, resulting in genome instability and blockade of proliferation. Resistant cells remain in mitotic block, and, upon drug decay, resume mitosis and proliferation, underlying one resistance mechanism. In our study we explored the possibility of forced mitotic exit to elevate Taxane efficacy. Inactivation of the SAC component, mitotic checkpoint kinase Mps1/TTK with a small molecule inhibitor (Msp1i), potentiated efficacy of Taxanes treatment in both 2D cell culture and 3D prostasphere settings. Mechanistically, Mps1 inhibition forced mitotic catastrophe in cells blocked in mitosis by Taxanes. Androgen receptor (AR), the main driver of PC, is often mutated or truncated in mCRPC. Remarkably, Mps1i significantly potentiated CBZ cytotoxicity regardless of AR status, in both AR-WT and in AR-truncated CRPC cells. Overall, our data demonstrate that forced mitotic exit by Mps1 inhibition potentiates Taxanes efficacy. Given that several Mps1i's are currently in different stages of clinical trials, our results point to Mps1 as a new therapeutic target to potentiate efficacy of Taxanes in mCRPC patients.

Topics: Androgens; Bridged-Ring Compounds; Cell Cycle Proteins; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Receptors, Androgen; Taxoids

Taxanes are the most active chemotherapy agents in metastatic castration-resistant prostate cancer (mCRPC) patients; yet, resistance occurs almost invariably, representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients, but the mechanistic basis and biomarkers remain elusive.. To identify mechanisms and response indicators for the antitumor efficacy of taxane-platinum combinations in mCRPC.. Transcriptomic data from a publicly available mCRPC dataset of taxane-exposed and taxane-naïve patients were analyzed to identify response indicators and emerging vulnerabilities. Functional and preclinical validation was performed in taxane-resistant mCRPC cell lines and genetically engineered mouse models (GEMMs).. Metastatic CRPC cells were treated with docetaxel, cisplatin, carboplatin, the CXCR2 antagonist SB265610, and the BCL-2 inhibitor venetoclax. Gain and loss of function in culture of CXCR2 and BCL-2 were achieved by overexpression or siRNA silencing. Preclinical assays in GEMM mice tested the antitumor efficacy of taxane-platinum combinations.. Proliferation, apoptosis, and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival, and histopathology. Changes in CXCR2, BCL-2, and chemokines were analyzed by reverse transcriptase quantitative polymerase chain reaction and Western blot. Human expression data were analyzed using Gene Set Enrichment Analysis, hierarchical clustering, and correlation studies. GraphPad Prism software and R-studio were used for statistical and data analyses.. Transcriptomic data from taxane-exposed human mCRPC tumors correlate with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated in experimental models that the sensitivity to cisplatin is dependent on CXCR2 and BCL-2, and that targeting them sensitizes prostate cancer (PC) cells to cisplatin. In vivo taxane-platinum combinations are highly synergistic, and previous exposure to taxanes sensitizes mCRPC tumors to second-line cisplatin treatment.. The hitherto unappreciated attenuation of the CXCR2/BCL-2 axis in taxane-treated mCRPC patients is an acquired vulnerability with potential predictive activity for platinum-based treatments.. A subset of patients with aggressive and therapy-resistant prostate cancer benefits from taxane-platinum combination chemotherapy; however, we lack the mechanistic understanding of how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell escape mechanisms to chemotherapy-induced cell death, hence making these cells more vulnerable to additional platinum treatment.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Cisplatin; Docetaxel; Humans; Male; Mice; Platinum; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-bcl-2; Taxoids

The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated.. Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell-free DNA, along with a matched germline sample, underwent targeted next-generation sequencing using a validated, highly sensitive in-house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes.. Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate-specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1 vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02).. These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard-of-care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.

Topics: Aged; Aged, 80 and over; Androgen Receptor Antagonists; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Humans; Male; Middle Aged; Nuclear Receptor Coactivator 2; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Survival Rate; Taxoids

In total, 95 prostate cancer (Pca) patients who underwent transurethral resection of the prostate from 2000 to 2013 were assigned to four groups: Group 1, hormone-naïve and T1a or T1b Pca (n = 17); Group 2, hormone-sensitive and metastatic Pca (n = 33); Group 3, chemo-naïve castration-resistant Pca (CRPC), (n = 18); and Group 4, CRPC with chemotherapy (n = 27). Full-length androgen receptor (ARfl) transcript levels significantly increased from Group 1 through to Group 3 (p = 0.045), but decreased from Group 3 through to Group 4. AR splice variant 7 (ARV7) and glucocorticoid receptor (GR) transcript levels significantly increased from Group 1 through to Group 4 (p = 0.002 and 0.049, respectively). Kaplan-Meier curve revealed that the high transcript level of these three receptors resulted in significantly poorer cancer-specific survival (CSS) than that by low transcript level, although Cox regression analysis revealed that the ARV7 level alone was an independent prognostic factor for CSS in CRPC patients (high vs. low: hazard ratio, 1.897; 95% confidence interval, 1.102-3.625; p = 0.042). In conclusion, ARV7 and GR transcript levels significantly increase as Pca progresses to CRPC.

Topics: Aged; Aged, 80 and over; Alternative Splicing; Bridged-Ring Compounds; Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Male; Organ Specificity; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Receptors, Glucocorticoid; Regression Analysis; Survival Analysis; Taxoids; Treatment Outcome

Compared to intravenous taxane chemotherapy, newer orally-available and/or less toxic agents for metastatic castration-resistant prostate cancer (MCRPC) may be associated with higher likelihood of starting treatment in patients with adverse prognostic features and limited life expectancy. To test this hypothesis, we analyzed the rates of treatment initiation during the last 30 days of life in a real-world cohort of men with MCRPC.. This was a retrospective analysis of 146 patients.. Seven patients (5%) who started any systemic treatment during the last 30 days of life were identified. The likelihood of treatment initiation in the last 30 days of life correlated significantly with the number of lines of systemic treatment (higher risk for previously treated patients) and non-use of bone-targeted agents.. Initiation of systemic therapy in the last 30 days of life was uncommon. This endpoint might complement other quality-of-care indicators.

Topics: Aged; Bridged-Ring Compounds; Disease-Free Survival; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prognosis; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Terminal Care; Treatment Outcome

Topics: Aged; Aged, 80 and over; Bridged-Ring Compounds; Dipeptides; Heterocyclic Compounds, 1-Ring; Humans; Ligands; Lutetium; Male; Neoplasm Metastasis; Progression-Free Survival; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Safety; Taxoids; Time Factors; Treatment Outcome

TMPRSS2-ERG expression in blood has been correlated with low docetaxel benefit in metastatic castration-resistant prostate cancer (mCRPC). This multicenter study aimed to prospectively asses its role as a taxane-resistance biomarker in blood and retrospectively in tumors, exploring also the impact of prior abiraterone/enzalutamide (A/E) in patients and in vitro. TMPRSS2-ERG was tested by quantitative reverse-transcription PCR. We included 204 patients (137 blood and 124 tumor samples) treated with taxanes. TMPRSS2-ERG expression was correlated with prostate-specific antigen (PSA)-progression-free survival (PFS), radiological-PFS (RX-PFS), and overall survival (OS). Independent association with survival was evaluated by multivariate Cox modeling. In vitro ERG knockdown and combinatorial and sequential experiments with enzalutamide and docetaxel were performed in VCaP cells. Prior A/E (HR 1.8, 95% CI 1.2-2.8) and blood TMPRSS2-ERG detection (HR 2, 95% CI 1.1-3.7) were independently associated to lower PSA-PFS. In patients without prior A/E, blood and tumor TMPRSS2-ERG independently predicted lower PSA-PFS (HR 3.3, 95% CI 1.4-7.9 and HR 1.8, 95% CI 1.02-3.3, respectively) to taxanes. When prior A/E was administered, TMPRSS2-ERG was not associated with outcome. There was a significant interaction between blood TMPRSS2-ERG and prior A/E related to PSA-PFS (p = 0.032) and RX-PFS (p = 0.009). In vitro stable ERG inhibition did not sensitize VCaP cells to docetaxel. Concomitant enzalutamide and taxanes were synergistic, but prior enzalutamide reduced docetaxel cytotoxicity in VCaP cells. Enzalutamide induced the expression of neuroendocrine markers and reduced that of E-cadherin. We conclude that prior hormone-therapy may influence taxanes response and TMPRSS2-ERG prognostic value. Thus, multiple and sequential biomarkers are needed in CRPC follow-up evaluation.

Topics: Benzamides; Biomarkers, Tumor; Bridged-Ring Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Disease-Free Survival; Docetaxel; Drug Resistance, Neoplasm; Drug Synergism; Gene Knockout Techniques; Humans; Male; Nitriles; Oncogene Proteins, Fusion; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Taxoids; Transcriptional Regulator ERG

Prostate-specific membrane antigen (PSMA) is a rational target for noninvasive detection of recurrent prostate cancer (PCa) and for therapy of metastatic castration-resistant prostate cancer (mCRPC) with PSMA-targeted agents. Here we conducted serial measurements of PSMA expression on circulating tumor cells (CTCs) to evaluate patterns of longitudinal PSMA dynamics over the course of multiple sequential therapies.. A retrospective investigation of men with mCRPC undergoing evaluation at medical oncology clinics at our institution assessed the dynamics of PSMA expression in the context of different systemic treatments administered sequentially. Eligibility included patients who began systemic therapies with androgen receptor (AR)-directed agents or taxane agents for whom peripheral blood samples were tested for CTC mRNA of AR splice variant-7 (AR-V7), prostate-specific antigen (PSA), and PSMA (with >2 CTC + results) in a CLIA-accredited laboratory.. From August 2015 to November 2017, we identified 96 eligible men. Fifteen had greater than or equal to 2 sequential therapies and evaluable CTC samples, greater than or equal to 1 expressing PSMA (PSMA+). Among the 15 patients included in this analysis, a total of 54 PSMA status evaluations were performed in the context of 48 therapies during a median follow-up of 18 months. At baseline, PSMA signal was detected ("positive") in 11 of 15 (73.3%) patients, while for 4 of 15 (26.7%) patients PSMA signal was undetectable ("negative"). In all but two patients, the baseline collection corresponded with a change in treatment. On the second assessment, PSMA increases were detected in all 4/4 (100%) PSMA-negative patients and 8 of 11 (72.7%) PSMA-positive patients. PSMA significantly decreased in a patient treated with. PSMA expression in CTCs is a dynamic marker. PSMA transcript declines appear to be associated with concurrent decreases in serum PSA. Sequential CTC sampling could provide a noninvasive response assessment to systemic treatment for mCRPC.

Topics: Aged; Aged, 80 and over; Antigens, Surface; Bridged-Ring Compounds; Dipeptides; Glutamate Carboxypeptidase II; Heterocyclic Compounds, 1-Ring; Humans; Lutetium; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Pilot Projects; Prostate-Specific Antigen; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; RNA, Messenger; Taxoids; Treatment Outcome

Resistance mechanisms in the androgen receptor (AR) signaling pathway remain key drivers in the progression to castration-resistant prostate cancer (CRPC) and relapse under antihormonal therapy.. We evaluated the circulating AR gene copy number (CN) gain using droplet digital polymerase chain reaction in 21 control and 91 prostate cancer serum samples and its prognostic and therapeutic implications in prostate cancer.. In CRPC, AR CN gain was associated with faster progression to CRPC (P = .026), a greater number of previous treatments (P = .045), and previous chemotherapy (P = .016). Comparing patients with and without CN gain, the median progression-free survival (PFS) in the abiraterone subgroup was 1.7 months versus not reached (P = .004), and the median overall survival (OS) was 7 months versus 20.9 months (P = .020). In the enzalutamide subgroup, PFS was 1.7 versus 10.8 months (P = .006), and OS was 6.1 versus 16.5 months (P = .042). In the taxane subgroup, PFS was 3.2 versus 6.5 months (P = .093), and OS was 3.9 months versus not reached (P = .026). The presence of more AR copies correlated with shorter androgen deprivation (P = .002), abiraterone (P = .022), enzalutamide (P = .008), and taxane (P = .039) therapy.. Circulating AR CN gain predicts for a poor prognosis in CRPC. It is a promising biomarker predetermining rapid CRPC progression and predicting worse abiraterone and enzalutamide outcomes. Furthermore, it is associated with multiple previous treatments and previous chemotherapy.

Topics: Aged; Androstenes; Benzamides; Bridged-Ring Compounds; Disease Progression; Disease-Free Survival; DNA, Neoplasm; Gene Dosage; Humans; Male; Middle Aged; Nitriles; Phenylthiohydantoin; Polymerase Chain Reaction; Prognosis; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Retrospective Studies; Taxoids

A blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or taxane is an unmet medical need.. To determine whether a validated assay for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells can determine differential overall survival among patients with mCRPC treated with taxanes vs ARS inhibitors.. This blinded correlative study conducted from December 31, 2012, to September 1, 2016, included 142 patients with histologically confirmed mCRPC and who were treated at Memorial Sloan Kettering Cancer Center, The Royal Marsden, or the London Health Sciences Centre. Blood samples were obtained prior to administration of ARS inhibitors or taxanes as a second-line or greater systemic therapy for progressing mCRPC.. Overall survival after treatment with an ARS inhibitor or taxane in relation to pretherapy AR-V7 status.. Among the 142 patients in the study (mean [SD] age, 69.5 [9.6] years), 70 were designated as high risk by conventional prognostic factors. In this high-risk group, patients positive for AR-V7 who were treated with taxanes had superior overall survival relative to those treated with ARS inhibitors (median overall survival, 14.3 vs 7.3 months; hazard ratio, 0.62; 95% CI, 0.28-1.39; P = .25). Patients negative for AR-V7 who were treated with ARS inhibitors had superior overall survival relative to those treated with taxanes (median overall survival, 19.8 vs 12.8 months; hazard ratio, 1.67; 95% CI, 1.00-2.81; P = .05).. This study suggests that nuclear-localized AR-V7 protein in circulating tumor cells can identify patients who may live longer with taxane chemotherapy vs ARS inhibitor treatment.

Topics: Aged; Alternative Splicing; Androgen Receptor Antagonists; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; Cell Nucleus; Disease-Free Survival; Humans; Male; Middle Aged; Neoplastic Cells, Circulating; Prognosis; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

To compare the efficacy and tolerability of taxane and nontaxane therapy in senior adults with chemonaïve metastatic castration-resistant prostate cancer (mCRPC), and examine the effect of patient health status on outcomes.. Between 2009 and 2011, 333 patients aged≥70 years with mCRPC were enrolled in a prospective international registry. Patients were categorized as having received taxane-based or nontaxane therapy, and classified as fit, vulnerable, frail, or terminal, according to investigator judgement or International Society of Geriatric Oncology guidelines. Efficacy measures included overall survival (OS) and progression-free survival. Grade 3/4 toxicities were recorded. Predictors of OS were identified using multivariate Cox regression.. The proportions of fit/vulnerable/frail patients were 65%/14%/17% (International Society of Geriatric Oncology), and 39%/43%/17% (investigator). In single-factor analyses, taxane therapy improved OS (hazard ratio [95%CI] = 0.53 [0.30-0.93]; P = 0.027) and progression-free survival (hazard ratio [95% CI] = 0.55 [0.40-0.76]; P<0.001) vs. nontaxane therapy. Patients with frailty also benefited from taxane therapy (adapted regimen in 52%). In multivariate analysis, taxanes improved OS even with poor prognostic factors present (P = 0.017); age was unrelated to prognosis. Taxane therapy was well tolerated; most common grade 3/4 toxicities (taxane vs. nontaxane) were fatigue (17% vs. 4%), nausea/vomiting (14% vs. 5%) and neutropenia (10% vs. 1%).. The results of this nonrandomized, observational study suggest that first-line taxane therapy may benefit senior adults with mCRPC more than alternative therapies. Treatment decisions should not be based on chronological age.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Fatigue; Humans; International Cooperation; Kaplan-Meier Estimate; Male; Nausea; Neutropenia; Outcome Assessment, Health Care; Proportional Hazards Models; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Registries; Taxoids; Vomiting

Identification of cancer biomarkers that inform clinical decisions and reduce the use of ineffective therapies is a major goal of precision oncology. An abnormal splice variant of the androgen receptor, AR-V7, was recently found to confer resistance to novel hormonal therapies (abiraterone and enzalutamide) in men with metastatic castration-resistant prostate cancer (mCRPC), but did not negatively affect responses to taxane chemotherapies, suggesting that early use of chemotherapy may be a more effective option for AR-V7(+) patients.. We calculated the cost savings of performing AR-V7 testing in mCRPC patients prior to starting abiraterone/enzalutamide (and avoiding these drugs in AR-V7(+) men) versus treating all mCRPC patients empirically with abiraterone/enzalutamide (without use of the biomarker).. We determined that AR-V7 testing would result in substantial cost savings as long as the true prevalence of AR-V7 was >5%. In our prior studies, we estimated that approximately 30% of mCRPC patients may have detectable AR-V7 in circulating tumor cells (CTCs). In this population, upfront testing of AR-V7 status (at a price of $1,000 per test) would result in a net cost savings of $150 Million in the United States per year.. AR-V7 testing in mCRPC patients would be cost-beneficial when considering the current price of treatment, and may reduce the ineffective use of abiraterone/enzalutamide, leading to a significant net cost savings to the healthcare system. Clinical-grade AR-V7 testing is currently available at our institution. Prostate 76:1484-1490, 2016. © 2016 Wiley Periodicals, Inc.

Topics: Androstenes; Benzamides; Biomarkers; Bridged-Ring Compounds; Cost Savings; Costs and Cost Analysis; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

Chemotherapy is an integral part of the treatment of castration resistant prostate cancer. With the introduction of new drugs the need to identify nonresponders is increasing. To our knowledge there are no prognostic parameters to date for use upon the initiation of any treatment.. cfDNA was isolated from a serum specimen before chemotherapy. Its value was correlated to recurrence-free and overall survival using Kaplan-Meier curves. Univariate and multivariate Cox regression analysis was performed to identify independent predictors.. Of 59 men 48 (81.4%) had a measurable prostate specific antigen decrease from baseline. Median followup was 15.0 months (range 2.4 to 58.4). The median cfDNA concentration in all men in this study was 27.71 ng/ml (mean 32.64). A threshold of 55.03 ng/ml was significantly associated with a poor prostate specific antigen response of less than 30% (p = 0.005). On univariate and multivariate analysis circulating cfDNA was an independent predictor of overall survival (HR 0.36, 95% CI 0.13-0.97, p = 0.044 and HR 0.34, 95% CI 0.12-0.91, p = 0.032, respectively). Limitations of the study are its retrospective character, and first and second line therapies.. Our trial shows that the cfDNA concentration before therapy may be a useful predictive and prognostic biomarker for prostate specific antigen response and survival.

Topics: Aged; Antineoplastic Agents; Biomarkers, Tumor; Bridged-Ring Compounds; DNA, Neoplasm; Humans; Male; Middle Aged; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Retrospective Studies; Survival Rate; Taxoids

Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

Topics: Androstenes; Androstenols; Benzamides; Bridged-Ring Compounds; Docetaxel; Drug Resistance, Neoplasm; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Isoforms; Receptors, Androgen; Taxoids

Castration-refractory prostate cancer (CRPC) is treated with taxane-based chemotherapy, but eventually becomes drug resistant. It is thus essential to identify novel therapeutic targets for taxane resistance in CRPC patients. We investigated the role of the chemokine (C-C motif) receptor 1 (CCR1) and its ligand, chemokine (C-C motif) ligand 5 (CCL5), in taxane-resistant CRPC using paclitaxel-resistant prostate cancer cells (PC3PR) established from PC3 cells. We found that the expression levels of CCR1 mRNA and protein were up-regulated in PC3PR cells compared to PC3 cells. In order to investigate the role of increased CCR1 in PC3PR cells, we stimulated cells with CCL5, one of the chemokine ligands of CCR1. In CCL5-stimulated PC3PR cells, siRNA-mediated knockdown of CCR1 expression reduced phosphorylation of ERK1/2 and Rac1/cdc42. Furthermore, CCR1 knockdown and MEK1/2 inhibition decreased CCL5-stimulated secretion of MMPs 2 and 9, which play important roles in cancer cell invasion and metastasis. In the Matrigel invasion assay, knockdown of CCR1 and inhibition of the ERK and Rac signaling pathways significantly decreased the number of invading cells. Finally, the serum CCL5 protein level as measured by ELISA was not different among the three groups of patients: those with negative prostate biopsy, those at initial diagnosis of prostate cancer, and those with taxane-resistant prostate cancer. These results demonstrated for the first time that the interaction of CCR1 with CCL5 caused by increased expression of CCR1 promotes invasion of PC3PR cells by increasing secretion of MMPs 2 and 9 and by activating ERK and Rac signaling. Our findings suggest that CCR1 could be a novel therapeutic target for taxane-resistant CRPC.

Topics: Aged; Bridged-Ring Compounds; cdc42 GTP-Binding Protein; Cell Line, Tumor; Cell Movement; Chemokine CCL5; Drug Resistance, Neoplasm; Extracellular Signal-Regulated MAP Kinases; Humans; Male; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Prostatic Neoplasms, Castration-Resistant; Proto-Oncogene Proteins c-akt; rac1 GTP-Binding Protein; Receptors, CCR1; RNA Interference; RNA, Messenger; RNA, Small Interfering; Taxoids