Indirect comparisons of triplet therapy as compared to novel hormonal therapy doublets in patients with metastatic castration sensitive prostate cancer.
Authors: Naqvi Syed Arsalan Ahmed , Riaz Zaryab Bin , Riaz Anum , Islam Mahnoor , Siddiqi Rabbia , Ikram Waleed , Bin Zafar Muhammad Daim , Singh Parminder , Riaz Irbaz Bin , Bryce Alan Haruo 
Published: June 2022

5083 Background: ARASENS and PEACE-1 trials suggests treatment intensification with novel hormonal therapy (NHT) in addition to androgen deprivation therapy (ADT) and docetaxel (DOC) provides survival benefit as compared to DOC+ADT in patients with metastatic castration sensitive prostate cancer (mCSPC). However, the performance of triplet therapy as compared to NHT+ADT remains unexplored. Methods: MEDLINE, EMBASE and recent conference proceedings were searched to include phase III trials evaluating triplet therapy in patients with mCSPC and reporting treatment effects in subgroup of patients with and without docetaxel. Outcomes included overall survival (OS) and radiographic progression free survival (rPFS). Precomputed hazard ratios (HRs) and confidence intervals (CIs) from non-randomized subgroup comparisons were pooled after logarithmic transformation using inverse-variance weighting approach. A DerSimonian-Laird random-effects meta-analysis was then performed to assess subgroup differences. Interaction between subgroups was assessed using P-value of heterogeneity. Mixed treatment comparisons were computed using a fixed-effect model within the frequentist framework using subgroup effect estimates from eligible trials. Results: This meta-analysis included five clinical trials (ARASENS, PEACE-1, ENZAMET, ARCHES and TITAN) with a total of 5804 patients (docetaxel: 2836; no docetaxel: 2836). Subgroup analysis showed statistically significant difference between treatment effects in patients who received docetaxel (NHT + DOC + ADT; HR: 0.74; 95% CI: 0.66-0.84; I2: 0%) and those who did not (NHT + ADT; HR: 0.61; 95% CI: 0.53-0.70; I2: 0%) for OS (p-value of interaction: 0.04). However, no statistically significant interaction was observed in terms of rPFS (p-value: 0.46). Mixed treatment comparisons showed improved OS with NHT + DOC + ADT (HR: 0.74; 95% CI: 0.66-0.84) as compared to DOC + ADT, but not when compared to NHT + ADT (HR: 0.97; 95% CI: 0.78-1.20). NHT + ADT significantly improved OS compared to DOC + ADT (HR: 0.77; 95% CI: 0.64-0.92). Consistently, significant rPFS improvement was observed with NHT + DOC + ADT when compared DOC + ADT (HR: 0.49; 95% CI: 0.42-0.57) but not when compared to NHT + ADT (HR: 0.82; 0.65-1.04). NHT + ADT was observed to improve rPFS compared to DOC + ADT (HR: 0.60; 95% CI: 0.50-0.72). Conclusions: This exploratory and hypothesis generating analysis suggests that addition of docetaxel (triplet therapy) may not delay progression or prolong survival compared to NHT-based doublets. These findings provide direction for future clinical trials in this space and suggest an equipoise to the question of how triplet regimens compare with NHT-doublets. The results should be interpreted with caution as this analysis does not account for potential confounding relationships such as volume of disease.