To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers (mCRPC).
In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone and apalutamide (AAPA; Module 1), then allocated to Modules 2 or 3 based on Satisfactory (≥50% PSA decline from baseline and <5 CTC/7. 5 mL) versus Unsatisfactory status. Men in the former were randomized to continue AAPA alone (Module 2A) or with ipilimumab (Module 2B). Men in the latter had carboplatin+cabazitaxel added to AAPA (Module 3). Optional baseline biopsies were subject to correlative studies.
Median overall survival (from allocation) was 46.4 (95% 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 pre-treatment 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 SPP1+ and IGFBP2+ 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 mCRPC. 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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Apr 29 [Epub ahead of print]
Ana M Aparicio, Rebecca S S Tidwell, Shalini S Yadav, Jiun-Sheng Chen, Miao Zhang, Jingjing Liu, Shuai Guo, Patrick G Pilie, Yao Yu, Xingzhi Song, Haswanth Vundavilli, Sonali Jindal, Keyi Zhu, Paul V Viscuse, Justin M Lebenthal, Andrew W Hahn, Rama Soundararajan, Paul G Corn, Amado J Zurita, Sumit K Subudhi, Jianhua Zhang, Wenyi Wang, Chad Huff, Patricia Troncoso, James P Allison, Padmanee Sharma, Christopher J Logothetis
The University of Texas MD Anderson Cancer Center, Houston, TX, United States., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., UT M D Anderson Cancer Center, Houston, TX, United States., The University of Texas MD Anderson Cancer Center, Houston, United States., The University of Texas MD Anderson Cancer Center, United States., University of Virginia, Charlottesville, United States., MD Anderson, Houston, Tx, United States., The University of Texas MD Anderson Cancer Center, Houston.