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Clinical activity of enzalutamide in Docetaxel-naive and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer.

ABSTRACT: Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.We aimed to examine the impact of prior D treatment on the clinical activity of enzalutamide in patients with mCRPC. We retrospectively reviewed an institutional database to identify men with mCRPC treated with standard-of-care enzalutamide. Patients were classified as D-naïve or D-pretreated. The efficacy end points were prostate-specific antigen (PSA) response rates (??50% PSA decline), time to PSA progression (TTPP) and clinical/radiographic progression-free survival (PFS) in response to enzalutamide. Differences between groups (D-naïve and D-pretreated) were assessed by univariate and multivariable analyses using logistic and Cox regression models.One-hundred-seven (107) consecutive patients were included: 60 were D-pretreated and 47 were D-naïve. PSA responses were 43.2% in D-naïve patients and 25.4% in D-pretreated patients (P?=?0.089). Median TTPP was 7.2 months (95% CI?=?4.5?-?17.2) in the D-naïve group versus 2.6 mo (95% CI?=?1.9?-?3.5) in the D-pretreated group (P?

SUBMITTER: Nadal R

PROVIDER: S-EPMC4176523 | biostudies-other | 2014 Nov

REPOSITORIES: biostudies-other

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Clinical activity of enzalutamide in Docetaxel-naïve and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer.

Nadal Rosa R Zhang Zhe Z Rahman Hibba H Schweizer Michael T MT Denmeade Samuel R SR Paller Channing J CJ Carducci Michael A MA Eisenberger Mario A MA Antonarakis Emmanuel S ES

The Prostate 20140831 15

<h4>Background</h4>Two randomized clinical trials have demonstrated a survival advantage with enzalutamide over placebo in both docetaxel (D)-pretreated and D-naïve metastatic castration-resistant prostate cancer (mCRPC) patients. Cross-resistance between androgen receptor-directed therapies and taxanes has been suggested, possibly leading to lower efficacy of enzalutamide in the post-D setting.<h4>Methods</h4>We aimed to examine the impact of prior D treatment on the clinical activity of enzalu ...[more]

PMID: 25176007

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Project description:BackgroundThe optimal sequencing of the multiple active agents now available for metastatic castration-resistant prostate cancer (mCRPC) is unclear. Prior reports have suggested diminished responses to sequential lines of androgen receptor (AR)-targeted therapies, but it is unknown whether subsequent taxane-based chemotherapy may be more effective than sequential AR-targeting treatment. We sought to evaluate the clinical activity of enzalutamide versus docetaxel in men with mCRPC who progressed on abiraterone.MethodsWe performed a single-institution retrospective analysis of consecutive mCRPC patients who had progressed on abiraterone therapy and subsequently received either enzalutamide (n=30) or docetaxel (n=31). We evaluated clinical outcomes including prostate-specific antigen decline of >30% (PSA30) or >50% (PSA50), PSA-progression-free survival (PSA-PFS), and clinical/radiographic PFS. We performed multivariable modeling to control for baseline and on-treatment differences between groups.ResultsCompared to subjects who received enzalutamide post-abiraterone, subjects who received docetaxel post-abiraterone had more bone metastases, more visceral metastases, higher baseline PSA, and had more frequent PSA tests while on-treatment. There were no significant differences in PSA30 (41% for enzalutamide vs. 53% for docetaxel) or PSA50 (34% vs. 40%) response rates between the two groups; there remained no difference after stratifying by presence/absence of prior response to abiraterone. Median PSA-PFS was 4.1 versus 4.1 months for the enzalutamide and docetaxel cohorts, respectively (HR 1.35, 95% CI, 0.53-3.66, P=0.502). Median PFS was 4.7 versus 4.4 months, respectively (HR 1.44, 95% CI, 0.77-2.71, P=0.257). PSA-PFS and PFS did not differ after stratifying by prior response to abiraterone. In multivariable analyses, there were no significant differences in PSA-PFS or PFS between the two groups.ConclusionsTreatment with either enzalutamide or docetaxel produced modest PSA responses and PFS intervals in this abiraterone-pretreated mCRPC population. In this retrospective study with small sample size, no significant differences in outcomes were observed between groups. Therefore, either enzalutamide or docetaxel may be a reasonable option in men who have progressed on abiraterone.

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: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.

Dataset Information

Clinical activity of enzalutamide in Docetaxel-naive and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer.

Publications

Clinical activity of enzalutamide in Docetaxel-naïve and Docetaxel-pretreated patients with metastatic castration-resistant prostate cancer.

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