Over the last decade, the sequencing and layering of treatments to optimize outcomes in castration-resistant prostate cancer (CRPC) has been a major focus of research. A critical question that we face is: How do we use clinical and molecular biomarkers to select patients for specific therapies? We are starting to see some progress in this area.

The phase 3 SPARTAN study showed that, in men with nonmetastatic CRPC (nmCRPC), apalutamide plus androgen deprivation therapy improved metastasis-free survival and overall survival compared with placebo plus androgen deprivation therapy. In abstract 8 from the 2021 Genitourinary Cancers Symposium, investigators sought to determine whether molecular signatures could distinguish between long-term responders and early progressors in the SPARTAN trial. After performing gene expression signatures on archival samples from 233 primary tumors, Feng and colleagues found that among the genes that predicted a longer-term response were those associated with a more activated immune system. In contrast, early progression on placebo was associated with high-risk disease, hormone nonresponsive tumors, and neuroendocrine-like tumors. These findings are interesting in that they generate hypotheses and spur important questions (eg, should patients with nmCRPC who are predicted to progress early on apalutamide follow an alternative treatment sequence?). Genomic testing with Decipher is not standard in this setting, and I would not suggest that patients should be selected for apalutamide using such testing based solely on this study. However, it is a nice illustration of how the use of a comprehensive genetic panel, along with clinical information, might further guide and individualize treatment.

Abstract 9 reported the final results of the ACIS study, a double-blind, placebo-controlled, phase 3 trial that evaluated the effectiveness of combining apalutamide and abiraterone plus prednisone vs placebo and abiraterone plus prednisone in nearly 1000 men with metastatic CRPC (mCRPC). This study demonstrated a 31% reduction in risk of radiographic progression-free survival with apalutamide and abiraterone plus prednisone, suggesting that targeting the androgen signaling pathway at different points may provide synergistic benefits. There was no significant difference in overall survival, but the data may not have been fully mature. Grade 3 or 4 treatment-emergent adverse events were reported in 63.3% of combination-treated men and in 56.2% of placebo with abiraterone plus prednisone–treated men; clearly, with combination therapy, there is the potential for an increased risk of side effects. For example, more potent androgen suppression might increase the risk for osteoporotic fractures. Additionally, it is unclear whether delaying progression, without producing an overall survival benefit, warrants the expense of combination treatment. However, if we could identify patients who are particularly sensitive to these pathways, we may be able to identify those who would benefit from combined therapy. In conclusion, while these findings are intriguing, further data are needed.

With respect to the sequencing of novel antihormonal therapies, we know that, in the community, there is quite a bit of second line, and perhaps even third line, use of these therapies in patients with mCRPC. In abstract 48, Sartor and colleagues conducted a retrospective analysis of the Flatiron electronic health record database to assess real-world clinical outcomes in patients with mCRPC who received sequential first-line/second-line treatment with abiraterone/enzalutamide or enzalutamide/abiraterone (n=226) and in patients with mCRPC who switched to radium-223 (Ra-223; n=120) after progression on first-line novel antihormonal therapy (NAH). The authors found a similar median overall survival (10.8 months for Ra-223 and 11.2 months for second-line NAH) and median treatment duration (5.6 months for Ra-223 and 4.7 months for second-line NAH) between both groups. The main takeaway was that NAH and Ra-223 had similar responses in the second-line setting. Still, as patients continue to progress on the limited number of active treatments available for mCRPC, especially in the third- and fourth-line settings, I encourage participation in clinical trials and limit the use of serial NAHs in mCRPC.