On-treatment serum prostate-specific antigen and overall survival in prostate cancer (STAMPEDE platform protocol): a post-hoc analysis of data from five phase 3 trials

BACKGROUND: Serum prostate-specific antigen (PSA) concentrations decrease after hormone therapy for prostate cancer, with the nadir serving as a potentially useful prognostic biomarker. To support clinical use, we evaluated the association between PSA nadir values and survival outcomes, stratified by pre-treatment metastatic volume or, in patients with non-metastatic cancer, stratified by lymph node status. METHODS: As part of the STAMPEDE platform trial, patients with metastatic or very high-risk non-metastatic prostate adenocarcinoma were recruited to five randomised, controlled, phase 3 trials conducted at 126 hospitals or oncology centres in Switzerland and the UK. Patients were randomly assigned to either standard of care (androgren deprivation therapy [ADT] alone or ADT plus docetaxel) or to one of five experimental treatment groups: ADT plus docetaxel with or without zoledronic acid, ADT plus abiraterone acetate with or without enzalutamide, or ADT plus prostate radiotherapy (only patients with metastatic disease). We used trial data from these participants to perform landmark analyses to test associations of PSA at 6, 12, and 24 weeks after randomisation with overall survival. Only patients with a PSA value were included in each landmark analysis. The Kaplan-Meier method was used to estimate 96-month overall survival rates and the corresponding 95% CIs for patients categorised by either metastatic volume or lymph node status. The STAMPEDE protocol platform is registered with ClinicalTrials.gov (NCT00268476), EUDRACT (2004-000193-31), and ISRCTN (ISRCTN78818544). FINDINGS: This study included 7129 patients from the STAMPEDE platform, who were recruited between Oct 5, 2005, and Sept 2, 2016; 4438 had metastases and 2691 had very high-risk non-metastatic disease. Among patients with metastasis and volumetric assessment, 2211 (55·9%) of 3956 had high-volume metastases, and among those with non-metastatic disease, 1033 (38·4%) were lymph node positive. A PSA concentration of 0·2 ng/mL or less was less frequent at 6 weeks or 12 weeks, but was associated with equivalent survival rates, compared with a PSA of 0·2 ng/mL or less at 24 weeks. Survival rates of PSA subcategories (≤0·2 ng/mL, >0·2 to 1·0 ng/mL, >1·0 to 3·0 ng/mL, and >3·0 ng/mL) differed by metastatic volume or, in patients with non-metastatic disease, by nodal status. Survival was longest for patients allocated to abiraterone with or without enzalutamide. Among patients with metastatic disease in the abiraterone with or without enzalutamide group who had a PSA of 0·2 ng/mL or less at 24 weeks, 96-month overall survival in patients with low-volume metastatic disease (64·1% [95% CI 57·8-69·8]) was higher than in patients with high-volume metastatic disease (44·6% [37·1-51·9]), but lower than in patients with non-metastatic, node-positive disease (79·4% [73·8-83·9]). 96-month overall survival was highest for patients with non-metastatic, node-negative disease (82·8% [95% CI 78·7-86·1]). INTERPRETATION: Metastatic volume or nodal status influence survival rates associated with on-treatment serum PSA categories, including for undetectable PSA. Radiological features and serum PSA could be combined to better predict survival. PSA at 24 weeks showed strongest associations with overall survival, although a PSA concentration of 0·2 ng/mL or less at any timepoint predicted favourable outcome. These findings could inform prognosis and warrant evaluation for treatment selection in clinical trials. FUNDING: Cancer Research UK, Prostate Cancer UK, UK Medical Research Council, and John Black Charitable Foundation.