Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials

Abstract

Background: Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours.

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 (p_interaction=0·0019), higher volume of metastases (p_interaction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (p_interaction=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.

Funding: UK Medical Research Council and Prostate Cancer UK.

Figure 1. Effect of docetaxel on progression-free survival by disease volume, timing of metastatic disease diagnosis, and clinical T stage at randomisation

The left-hand panel shows estimates of treatment effects within subgroups for individual trials, with boxes representing hazard ratios derived from Cox regression models fitted to each trial in turn, adjusted for the core covariate set and with missing covariate values imputed. The size of each square is directly proportional to the amount of information contributed by a trial, and the horizontal lines show the 95% CIs. The diamonds represent pooled estimates for each subgroup, derived using a within-trials framework, with the centre denoting the HR and the extremities the 95% CI. The filled circles on the right-hand panel show the interaction effects (ratio of hazard ratios) within each trial. These are derived from Cox regression models fitted to each trial in turn, including a treatment interaction term, and adjusted for the core covariate set and with missing covariate values imputed. Horizontal lines show the 95% CIs. Open circles show the meta-analysis interaction effect from two-stage, fixed-effect inverse-variance meta-analysis, with the centre denoting the hazard ratio and the extremities the 95% CI. ADT=androgen deprivation therapy.

Figure 2. Effect of docetaxel on progression-free survival and overall survival by volume and timing of metastatic disease diagnosis and by volume and clinical T stage

Relative effects of ADT plus docetaxel versus ADT alone by disease volume and timing of metastatic disease diagnosis combined on progression-free survival (A); disease volume and timing of metastatic disease diagnosis combined on overall survival (B); disease volume and clinical T stage combined on progression-free survival (C); and disease volume and clinical T stage combined on overall survival (D). Each diamond represents the pooled estimates for each subgroup, derived using a within-trials framework, with the centre denoting the hazard ratio and the extremities the 95% CI. ADT=androgen deprivation therapy.

Figure 3. Effect of docetaxel on progression-free survival and overall survival for patients with low-volume disease, by timing of metastatic disease diagnosis

Predicted survival curves for patients with low-volume metastatic disease for the subgroups of patients with synchronous and metachronous diagnosis, based on a one-stage flexible parametric meta-analysis model fitted to the entire participant sample with interaction terms between docetaxel effect and each of the four volume-by-timing subgroups, accounting appropriately for aggregation bias, adjusted for the core covariate set and with missing covariate values imputed, and using regression standardisation to estimate marginal progression-free survival curves for low-volume, metachronous disease (A); progression-free survival curves for low-volume, synchronous disease (B); overall survival curves for low-volume, metachronous disease (C); and overall survival curves for low-volume, synchronous disease (D). Red indicates ADT plus docetaxel and blue indicates ADT alone. Shaded areas denote the 95% CIs. ADT=androgen deprivation therapy.

Figure 4. Effect of docetaxel on progression-free survival and overall survival for patients with high-volume disease, by clinical T stage

Predicted survival curves for patients with high-volume metastatic disease, for subgroups based on clinical T stage, based on a one-stage flexible parametric meta-analysis model fitted to the entire participant sample with interaction terms between docetaxel effect and each of the four volume-by-stage subgroups, accounting appropriately for aggregation bias, adjusted for the core covariate set and with missing covariate values imputed, and using regression standardisation to estimate marginal progression-free survival curves for high-volume, T stage 1–3 (A); progression-free survival curves for high-volume, T stage 4 (B); overall survival curves for high-volume, T stage 1–3 (C); and overall survival curves for high-volume, T stage 4 (D). Shaded areas denote the 95% CIs. ADT=androgen deprivation therapy.