Data from A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration–Resistant Prostate Cancer

Abstract

<div>AbstractPurpose:<p>To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration–resistant prostate cancers.</p>Patients and Methods:<p>In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; <i>module 1</i>) and then allocated to <i>modules 2</i> or <i>3</i> based on <i>satisfactory</i> (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus <i>unsatisfactory</i> status. Men in the former were randomly assigned to continue AAPA alone (<i>module 2A</i>) or with ipilimumab (<i>module 2B</i>). Men in the latter group had carboplatin + cabazitaxel added to AAPA (<i>module 3</i>). Optional baseline biopsies were subjected to correlative studies.</p>Results:<p>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 <i>modules 2A</i> (<i>n</i> = 64), <i>2B</i> (<i>n</i> = 64), and <i>3</i> (<i>n</i> = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The <i>aggressive</i>-<i>variant prostate cancer</i> molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with <i>unsatisfactory</i> 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 <i>unsatisfactory</i> group.</p>Conclusions:<p>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 <i>unsatisfactory</i> 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.</p></div>