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

Autor:	Aparicio AM; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Tidwell RSS; Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas., Yadav SS; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas., Chen JS; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas., Zhang M; Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas., Liu J; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., Guo S; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas., Pilié PG; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Yu Y; Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas., Song X; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas., Vundavilli H; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., Jindal S; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas., Zhu K; Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas., Viscuse PV; Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., Lebenthal JM; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Hahn AW; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Soundararajan R; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas., Corn PG; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Zurita-Saavedra A; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Subudhi SK; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas., Zhang J; Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas., Wang W; Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas., Huff C; Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, Texas., Troncoso P; Department of Anatomical Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas., Allison JP; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas., Sharma P; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, Texas., Logothetis CJ; Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Jul 01; Vol. 30 (13), pp. 2751-2763.
DOI:	10.1158/1078-0432.CCR-23-3740
Abstrakt:	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. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
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