Editor's Note: Metastatic hormone-sensitive prostate cancer (mHSPC) is a heterogeneous disease state and represents a critical time window for improving survival in advanced prostate cancer, requiring comprehensive and personalized treatment. As diagnostic and therapeutic strategies continue to advance, the management and assessment of mHSPC have become increasingly complex. Several studies have already evaluated the efficacy of new regimens or drugs for mHSPC using radiographic progression-free survival (rPFS). Recently, a commentary published in the Journal of Clinical Oncology analyzed the feasibility of rPFS as a surrogate endpoint for evaluating mHSPC efficacy. This summary is presented for our readers.The STOPCaP study analyzed patient data from nine Phase III randomized trials, providing a comprehensive overview of the study’s strengths and limitations. This research suggests that rPFS could potentially serve as a surrogate endpoint in future clinical trials for metastatic hormone-sensitive prostate cancer (mHSPC). However, the researchers also noted that the findings are highly context-dependent and may influence the applicability of rPFS in current treatments and clinical trials.
The STOPCaP study included a total of 6,390 patients, 70.2% of whom received first-line androgen deprivation therapy (ADT). Because most patients were enrolled before 2010, when few effective treatments were available for metastatic castration-resistant prostate cancer (mCRPC), almost all FDA approvals occurred after 2010. In the ADT subgroup, the researchers found that rPFS from the two-stage META analysis met all three criteria, with the R2 for the second criterion of Condition 1 being 0.77 (95% CI, 0.40-0.96). The study also included 2,627 patients from four randomized controlled trials using ADT combined with docetaxel; in this subgroup, the second criterion of Condition 1 failed to demonstrate a strong correlation between 3-year rPFS and 5-year overall survival (OS), with an R2 of only 0.49.
As more effective treatment strategies emerge, many intermediate clinical endpoints (ICE) are no longer suitable as surrogate endpoints for OS. Recent studies, such as the THeraP trial and the PSMAfore trial in mCRPC patients, reflect this trend, with both trials showing that 177Lu-PSMA-617 improved rPFS (HRs of 0.64 and 0.43, respectively) but did not significantly improve OS. This lack of OS improvement is largely due to crossover use of treatment drugs and other effective therapies within the study population.
This trend was also observed in a large META analysis of 143 randomized trials in advanced prostate cancer (n=75,601 patients), including 34 trials (n=12,886 patients) focused solely on ADT in mHSPC patients. The R2 for PFS (not specifically rPFS) in Condition 2 was 0.58. The study further found a low correlation between treatment efficacy and subsequent treatment regimens. Among 68 randomized trials involving 27,845 advanced prostate cancer patients receiving chemotherapy, the correlation between efficacy and both PFS and OS was low (Condition 2: R2 0.36). Moreover, 17 trials (18,976 patients) found an even lower correlation for androgen receptor pathway inhibitors (Condition 2: R2 0.25). Notably, this previous study included both hormone-sensitive and castration-resistant patients, but similar trends were observed in both groups.
In summary, caution is warranted when considering rPFS as a uniform surrogate endpoint for OS in future mHSPC trials. It may be premature to adopt rPFS as a standardized endpoint. Of course, OS is not the only measure of patient benefit. Even if OS does not reach statistical significance, treatment strategies that reduce toxicity, lower patient costs, and improve ICE may still offer significant benefits to patients.
