Post-docetaxel Castration-resistant Prostate Cancer Research Articles

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study

BackgroundThere is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC.MethodsWe optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial).ResultsIn the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74–9.10; P < 0.001 and HR 3.81; 95% CI 2.28–6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08–4.39; P = 0.03, and HR 1.95; 95% CI 1.23–3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17–19.17; P = 0.035 and OR, 5.0; 95% CI 1.70–14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47–not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94–9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26–19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16–56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts.ConclusionPlasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required.Clinical Trial numberNCT02288936 (PREMIERE trial).

Efficacy of Abiraterone and Enzalutamide in Pre- and Postdocetaxel Castration-Resistant Prostate Cancer: A Trial-Level Meta-Analysis.

We examined the comparative efficacies of first-line abiraterone and enzalutamide in pre- and postdocetaxel settings in castration-resistant prostate cancer (CRPC) through a trial level meta-analysis. A mixed method approach was applied to 19 unique studies containing 17 median overall survival (OS) estimates and 13 median radiographic progression-free survival (PFS) estimates. We employed a random-effects meta-analysis to compare efficacies of abiraterone and enzalutamide with respect to OS and PFS. In the predocetaxel setting, enzalutamide use was associated with an increase in median OS of 5.9 months (p < 0.001), hazard ratio (HR) = 0.81, and an increase in median PFS of 8.3 months (p < 0.001), HR = 0.47 compared to abiraterone. The advantage of enzalutamide improved after adjusting for baseline Gleason score to 19.5 months (p < 0.001) and 14.6 months (p < 0.001) in median OS and PFS, respectively. In the postdocetaxel setting, the advantage of enzalutamide use was nominally significant for median PFS (1.2 months p = 0.02 without adjustment and 2.2 months and p = 0.0007 after adjustment); there was no significant difference in median OS between the two agents. The results from this comprehensive meta-analysis suggest a survival advantage with the use of first-line enzalutamide over abiraterone in CRPC and highlight the need for prospective clinical trials.

Long-term Safety and Antitumor Activity in the Phase 1–2 Study of Enzalutamide in Pre- and Post-docetaxel Castration-Resistant Prostate Cancer

BackgroundGiven that some patients with castration-resistant prostate cancer (CRPC) have shown extended responses to the androgen receptor inhibitor enzalutamide, long-term safety of this drug is of interest. ObjectiveTo evaluate the long-term safety and antitumor activity of enzalutamide in CRPC patients. Design, setting, and participantsThis phase 1–2 study evaluated enzalutamide in 140 CRPC patients with and without prior chemotherapy. Initial findings were published in 2010. We report updated results from an additional 17-mo follow-up for antitumor activity and >4 yr for safety. InterventionPatients received 30–600mg/d oral enzalutamide. During long-term dosing, all patients were switched first to the maximum tolerated dose of 240mg/d and then to the phase 3 dose of 160mg/d. Outcome measurements and statistical analysisSafety was assessed regularly. The Kaplan-Meier method was used to estimate the distributions of time to prostate-specific antigen (PSA) progression and time to radiographic progression. Results and limitationsThe safety profile of enzalutamide was consistent over time, with little change in the rates of commonly reported adverse events (AEs) or the incidence of grade 3/4 AEs. Fatigue of any grade was the most common dose-dependent AE, experienced by 70% of patients, with 14% of patients reporting grade 3/4 fatigue. The median time to PSA progression was not reached for chemotherapy-naive patients and was 45 wk for postchemotherapy patients; the corresponding median time to radiographic progression was 56 wk and 25 wk. ConclusionsEnzalutamide showed durable antitumor activity in chemotherapy-naive and postchemotherapy patients, and was well tolerated, even in patients treated for 4 yr. Patient summaryEnzalutamide was active against prostate cancer and was well tolerated, even for up to 4 yr of treatment, supporting its potential for long-term use in men with prostate cancer. Fatigue was the most common side effect, occurring at varying degrees of severity in most patients.

Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor.

4519^ Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) binding of androgens to AR, 2) AR nuclear translocation, and 3) association of AR with DNA. MDV3100 was active in a phase I-II trial enrolling pre- and post-docetaxel castration-resistant prostate cancer (CRPC) patients. The AFFIRM trial evaluated whether MDV3100 could provide benefit to men with post-docetaxel CRPC. Methods: In this double-blind, multinational phase III study, patients who had received docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients were stratified by baseline ECOG and mean brief pain inventory score. The primary endpoint was overall survival (OS). Other efficacy endpoints included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), soft tissue objective response (PR+CR), PSA response, and quality of life (QoL) response (FACT-P). Results: 800 patients were randomized to MDV3100 and 399 to placebo with respective median treatment durations of 8.3 and 3.0 months.Based on a planned interim analysis at 520 deaths, the Independent Data Monitoring Committee recommended the study be unblinded and placebo patients offered MDV3100. Efficacy results are presented (Table). The most common MDV3100 events with an incidence higher than placebo were fatigue (34% vs 29%), diarrhea (21% vs 18%), and hot flush (20% vs 10%). Grade &gt;3 events of interest were cardiac disorders (0.9% MDV3100 vs 2% placebo), fatigue (6% MDV3100 vs 7% placebo), seizure (0.6% MDV3100 vs. 0% placebo), and LFT abnormalities (0.4% MDV3100 vs 0.8% placebo). Conclusions: MDV3100, a novel ARSI, is well-tolerated and significantly prolongs OS, slows disease progression, and improves QoL in men with post-docetaxel CRPC. [Table: see text]

Efficacy of abiraterone acetate in post-docetaxel castration-resistant prostate cancer

Evaluation of: Reid AH, Attard G, Danila DC et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J. Clin. Oncol. 28(9), 1489–1495 (2010).Inhibition of cytochrome P17 (CYP17), which is involved in androgen synthesis, is a promising therapeutic strategy for castration-resistant prostate cancer (CRPC). The first multicenter, Phase II study of a CYP17 inhibitor, the small molecule abiraterone acetate, has been conducted on 47 patients that received prior docetaxel chemotherapy for prostate cancer. With 1000 mg once daily, declines of more than 50% in prostate-specific antigen and circulating tumor cell counts were seen in 51 and 63% of patients, respectively. Overall, the drug was well tolerated and had a significant antitumor activity with symptomatic improvements. Reid and colleagues’ study highlights abiraterone as a key molecule in CRPC treatment and gives further evidence of the involvement of the androgen receptor signaling axis in the disease. A randomized Phase III trial is ongoing to define the prognostic impact of this drug among the very limited arsenal of drugs currently available for CRPC. In the meantime, other CYP17 inhibitors are expected to show a favorable safety and efficacy profile, as are other novel powerful agents and combinatorial therapeutic strategies.

Phase II multicenter study of abiraterone acetate (AA) plus prednisone therapy in docetaxel-treated castration-resistant prostate cancer (CRPC) patients (pts): Impact of prior ketoconazole (keto)

5048 Background: AA is a potent blocker of CYP17, required for synthesis of testosterone in the testes, adrenals, and prostate tissue. Study objectives included confirming AA antitumor activity and safety in multicenter setting, describing changes in ECOG PS, and comparing keto-naïve pts to keto-exposed pts. Methods: The 58 pts had progressive, metastatic CRPC and had failed hormonal therapy and up to two cytotoxic regimens, including docetaxel. AA (1,000 mg QD) and prednisone (5mg BID) were administered daily, the registration trial regimen. 56/58 pts had available data. Results: Baseline demographics: median age - 69.0 (44–86) yrs; median PSA - 151.00 (10.0–3846.0) ng/mL; ECOG 0 (n = 23), 1 (n = 30), 2 (n = 2), missing (n = 1); median prior hormonal therapies were 4 and chemo 1; 24 pts had prior keto, 32 pts were keto-naïve and 2 pts had no data on keto exposure. 45% pts had total maximal PSA decline ≥50%. Total maximal PSA decline (≥30%, ≥50% and ≥90%) in prior keto vs. keto-naïve pts was observed respectively, in: 10 (42%) vs. 20 (63%) pts; 8 (33%) vs. 17 (53%); 1 (4%) vs. 10 (31%). From 32 pts with ECOG 1 or 2, 16 pts (50%, 95% CI 32–68) improved (PS 1 to 0 in 14 pts, PS 2 to 1 in 1 pt; PS 2 to 0 in 1 pt); 39 pts (64% of total 58 pts) maintained PS. Median time to PSA progression was 169 days (95% CI 82–200): keto-naïve-198 days, prior keto-99 days. The majority of AA-related adverse events (AEs) were grade 1–2. No AA-related grade 4 AE was noted. Conclusions: Abiraterone acetate was well-tolerated and produced anti-tumor activity in heavily pretreated pts, as evidenced by PSA declines and improved PS. Incidence of mineralocorticoid-related AEs (HTN or hypokalemia) was reduced with the addition of low-dose prednisone. The keto-naïve post-docetaxel CRPC population was selected for the ongoing phase III pivotal study to confirm these results. [Table: see text]