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Advances in hormonal therapies for hormone naive and castration-resistant prostate cancers with or without previous chemotherapy.

ABSTRACT: Hormonal manipulation plays a significant role in the treatment of advanced hormone naïve prostate cancer and castration-resistant prostate cancer (CRPC) with or without previous chemotherapy. Combination of gonadotropin releasing hormone (GnRH) agonists and androgen receptor (AR) antagonists (combined androgen blockade; CAB) is the first line therapy for advanced hormone naïve prostate cancer, but current strategies are developing novel GnRH antagonists to overcome disadvantages associated with GnRH agonist monotherapy and CAB in the clinical setting. Abiraterone acetate and enzalutamide are hormonal agents currently available for patients with CRPC and are both shown to improve overall survival versus placebo. Recently, in clinical trials, testosterone has been administered in cycles with existing surgical and chemical androgen deprivation therapies (ADT) (intermittent therapy) to CRPC patients of different stages (low risk, metastatic) to abate symptoms of testosterone deficiency and reduce cost of treatment from current hormonal therapies for patients with CRPC. This review will provide an overview on the therapeutic roles of hormonal manipulation in advanced hormone naïve and castration-resistant prostate cancers, as well as the development of novel hormonal therapies currently in preclinical and clinical trials.

SUBMITTER: Pham T

PROVIDER: S-EPMC4918127 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Advances in hormonal therapies for hormone naïve and castration-resistant prostate cancers with or without previous chemotherapy.

Pham Thy T Sadowski Martin C MC Li Huika H Richard Derek J DJ d'Emden Michael C MC Richard Kerry K

Experimental hematology & oncology 20150101

Hormonal manipulation plays a significant role in the treatment of advanced hormone naïve prostate cancer and castration-resistant prostate cancer (CRPC) with or without previous chemotherapy. Combination of gonadotropin releasing hormone (GnRH) agonists and androgen receptor (AR) antagonists (combined androgen blockade; CAB) is the first line therapy for advanced hormone naïve prostate cancer, but current strategies are developing novel GnRH antagonists to overcome disadvantages associated with ...[more]

PMID: 27340608

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Project description:IntroductionEnzalutamide significantly improved clinical outcomes compared with placebo in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) with disease progression despite androgen deprivation therapy (ADT) in the PREVAIL study. However, few patients from Asia were enrolled. Our study (NCT02294461) aimed to evaluate the safety and efficacy of enzalutamide in this disease setting in patients in mainland China, Korea, Taiwan, and Hong Kong.MethodsIn this double-blind, phase III study, patients with asymptomatic/mildly symptomatic metastatic prostate cancer and disease progression despite ADT were randomized to enzalutamide (160 mg/day) or placebo. The primary endpoint was time to prostate-specific antigen (PSA) progression. Secondary endpoints included overall survival, radiographic progression-free survival, time to first skeletal-related event (SRE), time to initiation of cytotoxic chemotherapy, PSA response ≥ 50%, best overall soft-tissue response, and safety. Pre-planned interim analysis was scheduled following approximately 175 PSA-progression events (67% of targeted total of 261 events). An additional 5-year landmark analysis of overall survival, time to antineoplastic therapy, and safety was performed.ResultsThe double-blind study period was stopped after interim analysis owing to the benefit of enzalutamide over placebo. Overall, 388 patients were randomized (enzalutamide, n = 198; placebo, n = 190). Baseline characteristics were balanced between treatment groups. Enzalutamide significantly reduced risk of PSA progression vs placebo (hazard ratio 0.38; 95% CI 0.27-0.52; P < 0.0001). Median time to PSA progression was 8.31 months with enzalutamide and 2.86 months with placebo. Secondary endpoints, including 5-year overall survival, were significantly improved with enzalutamide, except time to first SRE. Adverse-event incidence was similar between enzalutamide and placebo. Fatigue was the most common drug-related adverse event in both treatment groups.ConclusionEnzalutamide significantly reduced risk of PSA progression, improved secondary efficacy endpoints, and was well tolerated in chemotherapy-naïve Asian patients with mCRPC with disease progression despite ADT.Trial registrationwww.Clinicaltrialsgov NCT02294461.

Project description:Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy.Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients.This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial.Patients were grouped by concomitant BTT use or no BTT use.Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models.While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients.AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT.Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone.ClinicalTrials.gov NCT00887198.

Project description:BackgroundWe aimed to evaluate cost-effectiveness of enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer patients in Japan.MethodsA Markov model was developed to capture time spent by patients in various health states: stable, progression and death. Abiraterone acetate and docetaxel were set as active comparators. Clinical outcomes were obtained from the PREVAIL, COU-AA-302 and TAX327 trials. Treatment sequence, concomitant drugs and therapies for adverse events were estimated from responses to a survey by 14 Japanese prostate cancer experts. The analytic perspective was public healthcare payer, with a 10-year time horizon. The incremental cost-effectiveness ratio was estimated from quality-adjusted life-years and Japanese public healthcare costs. Probabilistic sensitivity analysis was performed to assess the robustness of the findings.ResultsAccording to the survey, the most common treatment sequences were (i) enzalutamide → docetaxel → cabazitaxel (enzalutamide-first sequencing), (ii) abiraterone → enzalutamide → docetaxel (abiraterone-first sequencing) and (iii) docetaxel→ enzalutamide → cabazitaxel (docetaxel-first sequencing). In the base-case analysis, enzalutamide-first sequencing saved 1.74 million Japanese Yen versus abiraterone-first sequencing, with a 0.129 quality-adjusted life-year gain (dominant). Enzalutamide-first sequencing had a cost increase of 4.44 million Japanese Yen over docetaxel-first sequencing, with a 0.371 quality-adjusted life-years gain. The incremental cost-effectiveness ratio of enzalutamide-first sequencing versus docetaxel-first sequencing was estimated as 11.94 million Japanese Yen/quality-adjusted life-years. Probabilistic sensitivity analyses demonstrated that, compared with abiraterone-first sequencing, enzalutamide-first sequencing had an 87.4% probability of being dominant.ConclusionsResults modeled herein suggest that the enzalutamide-first sequencing is more cost-effective than the abiraterone-first sequencing, but less cost-effective than docetaxel-first sequencing for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

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Advances in hormonal therapies for hormone naive and castration-resistant prostate cancers with or without previous chemotherapy.

Publications

Advances in hormonal therapies for hormone naïve and castration-resistant prostate cancers with or without previous chemotherapy.

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