Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial

Abstract

Background: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival.

Methods: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression).

Results: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity.

Conclusions: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.

Figure 1.

CONSORT diagram. M0 = nonmetastatic; N+ = node positive; N0 = node negative; SOC = standard of care; RT = radiotherapy;

Figure 2.

Metastatic progression-free survival by allocated treatment. Kaplan-Meier curves (solid line) and fitted flexible parametric model estimates (dashed line) for metastatic progression-free survival, by trial arm (hazard ratio [HR] = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .425).

Figure 3.

Other efficacy outcome measures by allocated treatment. Kaplan-Meier curves (solid line) and fitted flexible parametric model estimates (dashed line), by trial arm, for (A) failure-free survival; (B) progression-free survival; and (C) overall survival. D) shows the cumulative incidence function, by trial arm, for prostate cancer death (solid line) and nonprostate cancer death (dashed line). CI = confidence interval; HR = hazard ratio.

Figure 4.

Effect of standard-of-care (SOC) radiotherapy (RT), with or without docetaxel treatment. Results are shown for (A) failure-free survival, (B) progression-free survival, (C) metastatic progression-free survival (primary outcome), (D) overall survival, and (E) prostate cancer–specific survival. Left: Hazard/subhazard ratio with 95% confidence interval. Center: 5-year survival estimates, by arm. Right: Difference (RMST estimate) between SOC RT groups in survival time, where a positive difference indicates longer survival time for the subgroup planned for RT. RMST = restricted mean survival time.