In patients with metastatic castration-resistant prostate cancer (mCRPC), resistance to androgen receptor (AR) targeted therapies, such as enzalutamide, remains an issue. Inactivation of inhibitory phosphatase and tensin homolog (PTEN) activates phosphoinositide 3-kinase (PI3K)/AKT signaling and contributes to resistance to androgen-deprivation therapy and poor outcomes. Therefore, dual targeting of AR and PI3K/AKT pathways may limit tumor growth and reverse resistance.
In this Phase I study (NCT02215096), patients with PTEN-deficient mCRPC, who progressed on prior enzalutamide, received once-daily enzalutamide 160 mg plus PI3Kβ inhibitor GSK2636771 at 300 mg initial dose, with escalation or de-escalation in 100 mg increments, followed by dose expansion. Primary objectives were to evaluate safety/tolerability, determine the recommended Phase II dose (RP2D), and assess the 12-week non-progressive disease (PD) rate.
Overall, 37 patients were enrolled; 36 received {greater than or equal to}1 dose of GSK2636771 (200 mg: n=22, 300 mg: n=12; 400 mg: n=2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n=1; 300 mg: n=2, 400 mg: n=2). No new or unexpected adverse events nor evidence of drug-drug interaction were observed. At the recommended dose of GSK2636771 (200 mg) plus enzalutamide, the 12-week non-PD rate was 50% (95% CI: 28.2-71.8%, n=22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. 4/34 (12%) patients had prostate-specific antigen reduction of {greater than or equal to}50%.
Although there was acceptable safety and tolerability with GSK2636771 plus enzalutamide in patients with PTEN-deficient mCRPC after failing enzalutamide, limited antitumor activity was observed.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jul 19 [Epub ahead of print]
Debashis Sarker, Nancy A Dawson, Ana M Aparicio, Tanya B Dorff, Allan J Pantuck, Ulka N Vaishampayan, Lynn Henson, Lakshmi Vasist, Sumita Roy-Ghanta, Michele Gorczyca, Whitney York, Gopinath Ganji, Jerry Tolson, Johann S de Bono
Research Oncology, King's College London., Georgetown University., Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center., Department of Medical Oncology and Therapeutics research, City Of Hope National Medical Center., Urology, UCLA School of Medicine., Department of Medicine, University of Michigan Medical School., Global Safety, GSK., GSK., Clinical Biomarkers, GlaxoSmithKline (United States)., Clinical Operations Program Leadership, Biogen (United States)., Clinical Studies, Institute of Cancer Research .