Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476).

Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10-9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

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

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.

Quality of Life in Men With Prostate Cancer Randomly Allocated to Receive Docetaxel or Abiraterone in the STAMPEDE Trial.

PURPOSE: Docetaxel and abiraterone acetate plus prednisone or prednisolone (AAP) both improve survival when commenced alongside standard of care (SOC) androgen deprivation therapy in locally advanced or metastatic hormone-sensitive prostate cancer. Thus, patient-reported quality of life (QOL) data may guide treatment choices. METHODS: A group of patients within the STAMPEDE trial were contemporaneously enrolled with the possibility of being randomly allocated to receive either docetaxel + SOC or AAP + SOC. A mixed-model assessed QOL in those who had completed at least one QLQ-C30 + PR25 questionnaire. The primary outcome measure was difference in global-QOL (QLQ-C30 Q29&30) between patients allocated to docetaxel + SOC or AAP + SOC over the 2 years after random assignment, with a predefined criterion for clinically meaningful difference of > 4.0 points. Secondary outcome measures included longitudinal comparison of functional domains, pain, and fatigue, plus global-QOL at defined timepoints. RESULTS: Five hundred fifteen patients (173 docetaxel + SOC and 342 AAP + SOC) were included. Baseline characteristics, proportion of missing data, and mean baseline global-QOL scores (docetaxel + SOC 77.8 and AAP + SOC 78.0) were similar. Over the 2 years following random assignment, the mean modeled global-QOL score was +3.9 points (95% CI, +0.5 to +7.2; P = .022) higher in patients allocated to AAP + SOC. Global-QOL was higher for patients allocated to AAP + SOC over the first year (+5.7 points, 95% CI, +3.0 to +8.5; P < .001), particularly at 12 (+7.0 points, 95% CI, +3.0 to +11.0; P = .001) and 24 weeks (+8.3 points, 95% CI, +4.0 to +12.6; P < .001). CONCLUSION: Patient-reported QOL was superior for patients allocated to receive AAP + SOC, compared with docetaxel + SOC over a 2-year period, narrowly missing the predefined value for clinical significance. Patients receiving AAP + SOC reported clinically meaningful higher global-QOL scores throughout the first year following random assignment.

Docetaxel chemotherapy for metastatic hormone refractory prostate cancer as first-line palliative chemotherapy and subsequent re-treatment: Birmingham experience.

Three-weekly docetaxel chemotherapy with prednisolone is now considered standard of care for patients with metastatic hormone refractory prostate cancer (MHRPC). This study reports the efficacy and toxicity of first-line docetaxel chemotherapy followed subsequently by re-treatment on biochemical disease progression (BDP). Forty-two patients with MHRPC were treated with three-weekly docetaxel chemotherapy 75 mg/m(2) and 10 mg of prednisolone daily. Median age 73 years (range 58-87) and median initial PSA 182 ng/ml (range 19.9-1500). Of these patients, 10 were re-treated with the same regimen (second-line chemotherapy) on BDP. A further 3 out of these 10 patients received 2nd re-treatment (third-line chemotherapy) with docetaxel chemotherapy on BDP. Fifty-four percent of patients responded to first-line docetaxel chemotherapy and all re-treated patients responded again with a PSA reduction >50%. Median treatment-free interval prior to second and third-line chemotherapy was 24 and 26 weeks, respectively. Grade 3 or 4 neutropenia occurred in 2.5, 7 and 12% of the total number of cycles in patients receiving first-, second- and third-line docetaxel chemotherapy, respectively. Median survival was 13 months (range 3-35) and one-year overall survival 52%. This is the first report of three-weekly docetaxel chemotherapy re-treatment in patients with MHRPC and demonstrates that patients who initially respond to docetaxel chemotherapy maintain their sensitivity to subsequent re-treatment without a significant rise in haematological toxicity.

Time to prostate specific antigen (PSA) nadir may predict rapid relapse in men with metastatic castration-resistant prostate cancer (CRPC) receiving docetaxel chemotherapy.

Docetaxel has been shown to improve survival in patients with metastatic castrate-resistant prostate cancer (mCRPC). There is no clear consensus regarding the optimum duration of chemotherapy. If patients at greater risk of rapid disease relapse could be identified when on chemotherapy, appropriate follow-up strategies could be put into place. The aim of our study was to find prostate specific antigen (PSA) characteristics that predict a shorter disease response to docetaxel chemotherapy. Data from 41 consecutive mCRPC patients treated with three-weekly docetaxel chemotherapy at a single centre between February 2010 and February 2012 were retrospectively analysed. All patients had ≥50% reduction in their PSA with chemotherapy. The relationship between time to PSA nadir (TTN) and PSA halving time with time to PSA progression and overall chemotherapy response duration was analysed. TTN was a strong predictor of the duration of chemotherapy response and time to PSA progression. When TTN was ≥16 weeks, the mean duration of response to chemotherapy was 37.5 weeks compared to 19.9 weeks when TTN <16 weeks (95% CI, 12.66-22.60; p = 1.239 × 10(-8)). The mean time to PSA progression was 12.8 weeks if TTN was ≥16 weeks and 8.2 weeks TTN was <16 weeks (95% CI 0.63-8.60; p = 0.024). We observed that a TTN from the initiation of chemotherapy of <16 weeks for patients with mCRPC is an independent predictor of shorter duration of response and shorter progression-free survival.