Funding
Bristol Myers Squibb Foundation (BMSF)
National Institutes of Health (NIH)
UT MD Anderson Cancer Center Prostate Cancer Moonshot
MD Anderson Prostate Cancer Program
Conquer Cancer Foundation (CCF)
ARTICLE ABSTRACT
To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration–resistant prostate cancers.
In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies.
Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2–68.2], 41.4 (95% CI, 33.3–49.9), and 18.7 (95% CI, 14.3–26.3) months in modules 2A (n = 64), 2B (n = 64), and 3 (n = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The aggressive-variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with unsatisfactory status. Exploratory analyses suggested that secreted phosphoprotein 1–positive and insulin-like growth factor–binding protein 2–positive macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the unsatisfactory group.
Adding ipilimumab to AAPA did not improve outcomes in men with androgen-responsive metastatic castration–resistant prostate cancer. Despite the addition of carboplatin + cabazitaxel, men in the unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.
