Randomized controlled trials have usually excluded patients with a history of other cancers (HOC), because other cancers may affect survival endpoints, make the assessment of safety difficult, and reduce the homogeneity of the study population. However, this exclusion does not reflect real‐world practice, and the American Society of Clinical Oncology working group has recommended that such patients be included when the risk to endpoints is low [1]. In this context, the sub‐analysis of the ENABLE study by Hoshi et al. [2] is meaningful, because the study evaluates the impact of HOC on the outcomes of androgen receptor signaling inhibitors (ARSIs) in castration‐resistant prostate cancer (CRPC).
The main finding is reassuring. The HOC+ group showed shorter overall survival (OS) than the HOC‐ group (24.7 vs. 37.4 months), but prostate cancer‐specific survival, time to PSA progression, radiographic progression‐free survival, and adverse events were similar [2]. This suggests that enzalutamide (ENZ) and abiraterone (ABI) plus prednisolone are effective regardless of cancer history, and that the worse OS was caused by deaths from other cancers, not by treatment failure.
A more interesting finding is that, in the small HOC+ subgroup, ABI showed better OS than ENZ (30.5 vs. 16.0 months; HR: 3.27) [2]. However, this finding should be interpreted with caution for several reasons. First, the subgroup was very small (13 ENZ, 22 ABI), and many comparisons were made, so this may be a chance finding. Second, this result is opposite to previous large real‐world studies, which reported that ENZ was slightly better than ABI for OS [3, 4]. This supports the authors' interpretation that the OS difference was caused by baseline imbalance and early deaths from other cancers in the ENZ arm, not by a true difference between the drugs; in fact, prostate cancer‐specific survival did not differ between the arms. The authors also proposed the palliative effect of prednisolone and the difference in AR‐signaling suppression as possible mechanisms, but these are speculative and should be treated as hypothesis‐generating.
The main value of the ENABLE study is that it included HOC+ patients according to real‐world practice. This sub‐analysis suggests that the traditional exclusion criterion should be reconsidered. The difference between ABI and ENZ in HOC+ CRPC should be regarded as a hypothesis for future studies, not as a conclusion.
Author Contributions
The author takes full responsibility for this article.
Conflicts of Interest
The author declares no conflicts of interest.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.