TY - JOUR
T1 - A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer
AU - Aparicio, Ana M.
AU - Tidwell, Rebecca S.S.
AU - Yadav, Shalini S.
AU - Chen, Jiun Sheng
AU - Zhang, Miao
AU - Liu, Jingjing
AU - Guo, Shuai
AU - Pilié, Patrick G.
AU - Yu, Yao
AU - Song, Xingzhi
AU - Vundavilli, Haswanth
AU - Jindal, Sonali
AU - Zhu, Keyi
AU - Viscuse, Paul V.
AU - Lebenthal, Justin M.
AU - Hahn, Andrew W.
AU - Soundararajan, Rama
AU - Corn, Paul G.
AU - Zurita-Saavedra, Amado
AU - Subudhi, Sumit K.
AU - Zhang, Jianhua
AU - Wang, Wenyi
AU - Huff, Chad
AU - Troncoso, Patricia
AU - Allison, James P.
AU - Sharma, Padmanee
AU - Logothetis, Christopher J.
N1 - Publisher Copyright:
© 2024 American Association for Cancer Research.
PY - 2024/7/1
Y1 - 2024/7/1
N2 - Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers. Patients and Methods: 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. Results: 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. Conclusions: 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.
AB - Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers. Patients and Methods: 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. Results: 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. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85197958287&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-23-3740
DO - 10.1158/1078-0432.CCR-23-3740
M3 - Article
C2 - 38683200
AN - SCOPUS:85197958287
SN - 1078-0432
VL - 30
SP - 2751
EP - 2763
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -