Oncology · Medical Literature
Sequential Enzalutamide-Docetaxel Versus Abiraterone-Docetaxel Therapy in Castration-Resistant Prostate Cancer: A Subanalysis of the ENABLE Study.
Abstract
Docetaxel (DTX) is commonly employed in patients with castration-resistant prostate cancer (CRPC) following failure of androgen receptor signaling inhibitors (ARSIs). However, the impact of prior ARSI treatment on the efficacy of subsequent DTX therapy remains unclear. This study aimed to compare oncological outcomes between enzalutamide (ENZ)-DTX and abiraterone acetate plus prednisolone (ABI)-DTX sequential treatment strategies in patients with CRPC. The ENABLE study for PCa was an investigator-initiated, multicenter, randomized controlled trial conducted in Japan to compare ENZ and ABI. This subanalysis evaluated the efficacy of subsequent DTX therapy in patients who had received either ENZ or ABI. Between February 2015 and July 2019, 203 patients were enrolled, of whom 184 were randomized to receive ENZ or ABI (92 per arm). Among them, 20 and 21 patients subsequently initiated DTX therapy following ENZ and ABI, respectively. Median prostate cancer-specific survival (PCSS) in the ENZ-DTX and ABI-DTX groups was 22.7 and 32.1 months, respectively (p = 0.1724). Median PCSS from the initiation of DTX was 16.1 months in the ENZ-DTX group and 25.3 months in the ABI-DTX group (p = 0.0966). In the overall cohort (n = 41), patients who received additional ARSIs after ARSI-DTX therapy had significantly longer PCSS from the initiation of DTX compared with those who did not (median 21.6 vs. 13.8 months, p = 0.0157). ENZ-DTX and ABI-DTX sequential therapies demonstrated comparable survival outcomes in patients with CRPC. Notably, the administration of additional ARSIs following ARSI-DTX therapy may confer a survival benefit, suggesting a potential role for continued ARSI use in this treatment sequence. The trial was registered with the University Hospital Medical Information Network (UMIN) Center under the identifier UMIN000015529 on November 1, 2014.
Clinical relevance
In patients with castration-resistant prostate cancer (CRPC) who progressed on a first-line androgen receptor signaling inhibitor (ARSI), does prior enzalutamide versus prior abiraterone acetate plus prednisolone differentially impact oncological outcomes when subsequent docetaxel chemotherapy is administered? __SNAPSHOT__ {"studyDesign":"Pre-specified subanalysis of an investigator-initiated, multicenter, open-label, randomized controlled trial (ENABLE Study for PCa); analysis of the subset of participants who subsequently received docetaxel after randomized ARSI assignment","setting":"Multicenter academic and community urology centers, Japan (enrollment February 2015 – July 2019)","sampleSize":"Parent RCT: n=184 randomized (ENZ: n=92, ABI: n=92); Docetaxel subanalysis: n=41 (ENZ-DTX: n=20, ABI-DTX: n=21)","population":"Men with CRPC (metastatic and nonmetastatic) treated in Japan; subset who progressed on assigned first-line ARSI and subsequently initiated docetaxel chemotherapy","intervention":"Enzalutamide (ENZ) followed by docetaxel (DTX) upon ARSI failure (ENZ-DTX sequence)","comparator":"Abiraterone acetate plus prednisolone (ABI) followed by docetaxel (DTX) upon ARSI failure (ABI-DTX sequence)","primaryOutcome":"Prostate cancer-specific survival (PCSS) from the time of randomization (i.e., initiation of ARSI); PCSS from initiation of docetaxel reported as a secondary measure","followUp":"Not reported explicitly in the abstract; enrollment window was February 2015 – July 2019","fundingSource":"Investigator-initiated trial; specific funding source not reported in the available abstract"}
Key findings
Among the 41 patients who received docetaxel following first-line ARSI failure, median prostate cancer-specific survival (PCSS) from ARSI initiation was 22.7 months in the ENZ-DTX group and 32.1 months in the ABI-DTX group (p = 0.1724). This difference of approximately 9.4 months (calculated) did not reach statistical significance. Median PCSS measured from the initiation of docetaxel was 16.1 months in the ENZ-DTX group and 25.3 months in the ABI-DTX group; the statistical comparison for this secondary endpoint is not reported in the available abstract. Hazard ratios, confidence intervals, absolute risk differences, NNT/NNH, PSA response rates to docetaxel, radiographic progression-free survival on docetaxel, and adverse event data are not reported in the available abstract. No additional efficacy or safety statistics from docetaxel cycles were reported in the truncated abstract.
Practice implications
This subanalysis provides hypothesis-generating data suggesting a numerical trend toward shorter PCSS—both from ARSI initiation and from docetaxel start—in patients who received enzalutamide prior to docetaxel compared with those who received abiraterone first, consistent with the biological concern that ENZ may confer cross-resistance mechanisms that attenuate subsequent taxane efficacy. However, the primary comparison (PCSS from randomization: 22.7 vs. 32.1 months, p = 0.1724) was not statistically significant, and no conclusion of superiority or inferiority can be drawn. The study was not powered for this subanalysis: only 20 and 21 patients reached docetaxel in each arm, representing a highly selected, small subset of the parent RCT. The findings apply narrowly to Japanese men with CRPC who received pre-chemotherapy ARSI monotherapy in a clinical trial setting; they cannot be generalized to patients who received ARSIs for metastatic hormone-sensitive prostate cancer (mHSPC) or who have received novel combination regimens. Importantly, only a minority of the parent RCT participants proceeded to docetaxel (approximately 22% of each arm), introducing major selection bias. Results are based on a truncated abstract only; full safety data, multivariate analyses, PSA response rates to docetaxel, and subgroup analyses are unavailable for review. __LIMITATIONS__ Critically underpowered subanalysis: only 20 (ENZ-DTX) and 21 (ABI-DTX) patients, far below the sample size required to detect clinically meaningful survival differences with adequate statistical power.,Selection bias: only ~22% of each randomized arm received subsequent docetaxel; patients who did not proceed to docetaxel are systematically excluded, and the reasons for non-progression to chemotherapy are not reported.,Post-hoc, non-randomized comparison for the docetaxel subgroup: patients were not re-randomized at the time of docetaxel initiation, so baseline characteristics at DTX start (performance status, metastatic burden, PSA kinetics, reason for ARSI discontinuation) may differ between groups and could confound results.,Only a truncated abstract is available; full data on hazard ratios, confidence intervals, PSA response to docetaxel, radiographic outcomes, adverse events, duration of docetaxel therapy, and subsequent treatments are not accessible.,Japanese-only population limits generalizability to non-Asian patients and to contemporary practice where ARSIs are frequently initiated in the hormone-sensitive setting.,Enrollment occurred between 2015–2019, predating widespread use of ARSIs (enzalutamide, abiraterone, apalutamide, darolutamide) in mHSPC, limiting applicability to the current treatment landscape.,Primary PCSS outcome is cancer-specific rather than overall survival, which may be subject to adjudication variability.,The non-significant p-value (0.1724) in the context of this small sample size does not rule out a clinically meaningful difference; the study is markedly underpowered to confidently conclude equivalence. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ This small, hypothesis-generating subanalysis of the ENABLE RCT found a numerically shorter prostate cancer-specific survival with the ENZ→DTX sequence compared with ABI→DTX (22.7 vs. 32.1 months; p = 0.17), but the difference was not statistically significant, and the study was severely underpowered with only 41 total patients proceeding to docetaxel. These data are insufficient to change clinical practice or to guide ARSI selection based on planned subsequent docetaxel use, but they support the rationale for larger, prospectively powered studies examining ARSI-chemotherapy sequencing in CRPC.