Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data

Abstract

SummaryBackgroundResults from large randomised controlled trials combining docetaxel or bisphosphonates with standard of care in hormone-sensitive prostate cancer have emerged. In order to investigate the effects of these therapies and to respond to emerging evidence, we aimed to systematically review all relevant trials using a framework for adaptive meta-analysis.MethodsFor this systematic review and meta-analysis, we searched MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant randomised controlled trials (published, unpublished, and ongoing) comparing either standard of care with or without docetaxel or standard of care with or without bisphosphonates for men with high-risk localised or metastatic hormone-sensitive prostate cancer. For each trial, we extracted hazard ratios (HRs) of the effects of docetaxel or bisphosphonates on survival (time from randomisation until death from any cause) and failure-free survival (time from randomisation to biochemical or clinical failure or death from any cause) from published trial reports or presentations or obtained them directly from trial investigators. HRs were combined using the fixed-effect model (Mantel-Haenzsel).FindingsWe identified five eligible randomised controlled trials of docetaxel in men with metastatic (M1) disease. Results from three (CHAARTED, GETUG-15, STAMPEDE) of these trials (2992 [93%] of 3206 men randomised) showed that the addition of docetaxel to standard of care improved survival. The HR of 0·77 (95% CI 0·68–0·87; p<0·0001) translates to an absolute improvement in 4-year survival of 9% (95% CI 5–14). Docetaxel in addition to standard of care also improved failure-free survival, with the HR of 0·64 (0·58–0·70; p<0·0001) translating into a reduction in absolute 4-year failure rates of 16% (95% CI 12–19). We identified 11 trials of docetaxel for men with locally advanced disease (M0). Survival results from three (GETUG-12, RTOG 0521, STAMPEDE) of these trials (2121 [53%] of 3978 men) showed no evidence of a benefit from the addition of docetaxel (HR 0·87 [95% CI 0·69–1·09]; p=0·218), whereas failure-free survival data from four (GETUG-12, RTOG 0521, STAMPEDE, TAX 3501) of these trials (2348 [59%] of 3978 men) showed that docetaxel improved failure-free survival (0·70 [0·61–0·81]; p<0·0001), which translates into a reduced absolute 4-year failure rate of 8% (5–10). We identified seven eligible randomised controlled trials of bisphosphonates for men with M1 disease. Survival results from three of these trials (2740 [88%] of 3109 men) showed that addition of bisphosphonates improved survival (0·88 [0·79–0·98]; p=0·025), which translates to 5% (1–8) absolute improvement, but this result was influenced by the positive result of one trial of sodium clodronate, and we found no evidence of a benefit from the addition of zoledronic acid (0·94 [0·83–1·07]; p=0·323), which translates to an absolute improvement in ...

Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy

“…This is the sixth comparison in the trial for which we are reporting survival data 15,16,[24][25][26][27] and the first comparison incorporated after trial initiation. 22 The use of ADT plus abiraterone and prednisolone as compared with ADT alone was associated with a 71% relative improvement in the time to treatment failure, which translated into a 37% difference in overall survival.…”

“…Some future information will emerge from the STAMPEDE trial, which includes a further comparison involving abiraterone plus enzalutamide in which docetaxel was permitted as part of the standard of care in patients who had undergone randomization starting in 2016. The PEACE1 trial also now includes patients receiving docetaxel as part of the standard of care and will help address the question of whether the benefits seen with docetaxel [15][16][17] are overlapping or additional to those seen with abiraterone.…”

“…[12][13][14] We have previously reported that treatment with docetaxel at the inception of ADT increased median survival from 71 months to 81 months as well as overall survival (hazard ratio for death, 0.76). 15,16 These results, along with those of a systematic review that included other trials [17][18][19] and of a meta-analysis, 16 led to docetaxel becoming a part of the standard of care for suitable patients with prostate cancer who had not received previous hormone therapy.…”

Hormone naïve metastatic prostate cancer: can results of meta-analyses of aggregate data convince oncologists to expand the role of docetaxel?

“…The results of these trials and of a recent aggregated data meta-analysis (ADM) performed by the same investigators initiated a debate on the efficacy of this approach. [7] We conducted an aggregated data meta-analysis of reported phase III randomized controlled trials (RCTs) assessing the efficacy of this approach exclusively in patients with metastatic (M1) disease.…”

Will chemotherapy change the management of prostate cancer?

“…A meta-analysis including all three trials was published in December 2015 [7]. This includes data from 2992 men with metastatic disease, in this group docetaxel significantly improved survival at 4 years from 40% to 49%.…”