Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial

Mark C. Markowski (), Mary-Ellen Taplin, Rahul Aggarwal, Laura A. Sena, Hao Wang, Hanfei Qi, Aliya Lalji, Victoria Sinibaldi, Michael A. Carducci, Channing J. Paller, Catherine H. Marshall, Mario A. Eisenberger, David E. Sanin, Srinivasan Yegnasubramanian, Carolina Gomes-Alexandre, Busra Ozbek, Tracy Jones, Angelo M. Marzo, Samuel R. Denmeade and Emmanuel S. Antonarakis
Additional contact information
Mark C. Markowski: Johns Hopkins University
Mary-Ellen Taplin: Dana-Farber Cancer Institute
Rahul Aggarwal: University of California San Francisco
Laura A. Sena: Johns Hopkins University
Hao Wang: Johns Hopkins School of Medicine
Hanfei Qi: Johns Hopkins School of Medicine
Aliya Lalji: Johns Hopkins University
Victoria Sinibaldi: Johns Hopkins University
Michael A. Carducci: Johns Hopkins University
Channing J. Paller: Johns Hopkins University
Catherine H. Marshall: Johns Hopkins University
Mario A. Eisenberger: Johns Hopkins University
David E. Sanin: Johns Hopkins University
Srinivasan Yegnasubramanian: Johns Hopkins University
Carolina Gomes-Alexandre: Johns Hopkins School of Medicine
Busra Ozbek: Johns Hopkins School of Medicine
Tracy Jones: Johns Hopkins School of Medicine
Angelo M. Marzo: Johns Hopkins University
Samuel R. Denmeade: Johns Hopkins University
Emmanuel S. Antonarakis: Johns Hopkins University

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract Cyclic high-dose testosterone administration, known as bipolar androgen therapy (BAT), is a treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we report the results of a multicenter, single arm Phase 2 study (NCT03554317) enrolling 45 patients with heavily pretreated mCRPC who received BAT (testosterone cypionate, 400 mg intramuscularly every 28 days) with the addition of nivolumab (480 mg intravenously every 28 days) following three cycles of BAT monotherapy. The primary endpoint of a confirmed PSA50 response rate was met and estimated at 40% (N = 18/45, 95% CI: 25.7–55.7%, P = 0.02 one-sided against the 25% null hypothesis). Sixteen of the PSA50 responses were achieved before the addition of nivolumab. Secondary endpoints included objective response rate (ORR), median PSA progression-free survival, radiographic progression-free survival (rPFS), overall survival (OS), and safety/tolerability. The ORR was 24% (N = 10/42). Three of the objective responses occurred following the addition of nivolumab. After a median follow-up of 17.9 months, the median rPFS was 5.6 (95% CI: 5.4–6.8) months, and median OS was 24.4 (95% CI: 17.6–31.1) months. BAT/nivolumab was well tolerated, resulting in only five (11%) drug related, grade-3 adverse events. In a predefined exploratory analysis, clinical response rates correlated with increased baseline levels of intratumoral PD-1 + T cells. In paired metastatic tumor biopsies, BAT induced pro-inflammatory gene expression changes that were restricted to patients achieving a clinical response. These data suggest that BAT may augment antitumor immune responses that are further potentiated by immune checkpoint blockade.

Date: 2024
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DOI: 10.1038/s41467-023-44514-2

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