Methods
The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591.
Findings
We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55–85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9–11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (–1%, 95% CI –15 to 12, for progression-free survival; 0%, –10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival).
Interpretation
The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes.
Several strategies combining androgen deprivation treatment (ADT) with new hormonal agents (NHA) and/or docetaxel (D) are currently available as the standard care for men with metastatic hormone-sensitive prostate cancer (mHSPC). However, it is still a clinical challenge to select the most appropriate individual case-based approach in light of available contradictory evidence. Regarding the upfront chemohormonal therapy, CHAARTED yielded a survival benefit for patients with high-, but not for low-volume mHSPC. On the contrary, another milestone phase 3 trial STAMPEDE did not demonstrate an interaction of disease volume with D efficacy. In this context, meta-analyses of prospective randomised trials might overcome limitations of individual studies and provide clinically relevant insights.
Vale and collaborators performed a meta-analysis of individual participant data from GETUG-AFU15, CHAARTED and STAMPEDE including 2261 patients with a median follow-up of 72 months. Addition of D to ADT yielded a significant prolongation of overall survival (HR 0·79), progression-free survival (PFS; HR 0·70), and failure-free survival (HR 0·64), representing 5-year absolute improvements of around 9–11% as compared to ADT monotherapy. Further outcomes of radiological progression-free survival, prostate cancer–specific survival, time to PSA failure, and time to castrate-resistant disease all favoured addition of D to ADT with associated absolute differences in benefits of ca. 10% at 5 years Notably, disease volume and clinical T stage independently modified the effect of D on PFS after mutual adjustment, whereas timing of metastatic disease diagnosis did not. Importantly, clinical stage data were missing in 30% of metachronous and in 19% of synchronous cases. The largest absolute improvement at 5 years was observed for patients with high volume, clinical T stage 4 disease. In contrast, there was no evidence of a meaningful benefit for men with metachronous, low-volume disease.
The meta-analysis of Vale et al. corroborates the current practice of applying the upfront chemohormonal treatment preferentially in synchronous high-volume mHSPC. The main new finding is that clinical T stage might be a predictor for response of this therapy. However, far-reaching conclusions are limited by missing stage data in many cases particularly from GETUG-AFU15 as well as CHAARTED. Furthermore, accuracy of the clinical T stage classification in mHSPC in everyday practice is questionable, in metachronous disease even more than in synchronous one. All-in-all, the main question of which patients should receive D+ADT instead of NHA+ADT or even triple therapy remains unanswered so far. Since available evidence refutes an impact of disease volume or timing on the efficacy of NHA+ADT, which itself appears to outperform that of D+ADT according to meta-analyses, the clinical conundrum is nowadays more to choose between NHA+ADT and NHA+D+ADT than to opt for D+ADT.