Triplet versus doublet therapy in older patients with metastatic hormone-sensitive prostate cancer: A network meta-analysis.

Abstract

5088 Background: Multiple treatment options are now available for metastatic hormone-sensitive prostate cancer (mHSPC) with the expanded approval of androgen receptor axis-targeted (ARAT) agents. Comparing the therapeutic benefits of these treatments in older patients would contribute to selecting the optimal treatment for this population. Methods: We performed a systematic search of PubMed, Embase, Web of Science and Cochrane library for randomized controlled trials (RCTs) evaluating the efficacy of androgen deprivation therapy (ADT) in combination with ARAT agents and/or docetaxel in older patients (aged ≥70 or ≥75 years) with mHSPC. A network meta-analysis (NMA) was conducted to compare and rank the efficacy of the available treatment options. The first NMA compared four treatment classes, grouping ARATs as a single class: ARAT + ADT + docetaxel, ARAT + ADT, ADT + docetaxel, and ADT alone. The second NMA analyzed seven treatment options, treating different ARAT agents as independent regimens: two triplets (abiraterone or darolutamide) + ADT + docetaxel, three doublets (abiraterone, enzalutamide, or apalutamide) + ADT, ADT + docetaxel, and ADT alone. A random effects model was used to estimate hazard ratio (HR) for overall survival (OS) for each treatment. Results: 10 RCTs comprising 3,496 patients were analyzed. In the first NMA (grouping ARAT agents as a single class), triplet therapy was associated with a significant 30% lower risk of death compared to ADT + docetaxel (HR 0.70, 95% CI 0.50-0.96), and a non-significant 31% lower risk of death compared to ARAT + ADT (HR 0.69, 95% CI 0.43-1.11). In the second NMA (treating different ARAT agents as independent treatments), darolutamide + ADT + docetaxel was associated with a significant improvement in OS with HRs of 0.47 (95% CI: 0.28-0.78) and 0.61 (95% CI: 0.40-0.94) compared to ADT alone and doublet (ADT + docetaxel), respectively. However, the triplet of abiraterone + ADT + docetaxel was associated with a non-significant OS benefit, with HRs of 0.61 (95% CI 0.36-1.04) and 0.80 (95% CI 0.51-1.25) compared to ADT alone and ADT + docetaxel, respectively. The triplet therapies with darolutamide and abiraterone ranked first and second, with P score of 0.92 and 0.69, respectively, followed by apalutamide + ADT (0.62), enzalutamide + ADT (0.59), ADT + docetaxel (0.42), abiraterone + ADT (0.21) and ADT alone (0.05). Further, our data suggest a clear additional benefit from adding docetaxel as a component of doublet and triplet therapies, as shown by the superiority of ADT + docetaxel over ADT alone (P score 0.42 vs 0.05) and abiraterone + ADT + docetaxel over abiraterone + ADT (P score 0.69 vs 0.21). Conclusions: Triplet therapy of darolutamide + ADT + docetaxel should be prioritized over other treatment options for fit older patients with mHSPC. Further research utilizing real-world effectiveness data is essential to validate this recommendation.