☆ 4.7 Article

A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3K beta Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer

CLINICAL CANCER RESEARCH (2021)

Journal

CLINICAL CANCER RESEARCH

Volume 27, Issue 19, Pages 5248-5257

Publisher

AMER ASSOC CANCER RESEARCH

DOI: 10.1158/1078-0432.CCR-21-1115

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Abstract

The study investigated the combination of enzalutamide and the PI3K beta inhibitor GSK2636771 in patients with PTEN-deficient mCRPC. Results demonstrated acceptable safety and tolerability of the drug combination, but limited antitumor activity was observed.

Purpose: 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 PTEN activates 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. Patients and Methods: In this phase I study (NCT02215096), patients with PTEN-deficient mCRPC who progressed on prior enzalutamide received once-daily enzalutamide 160 mg plus PI3K beta 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, and assess the 12-week non-progressive disease (PD) rate. Results: Overall, 37 patients were enrolled; 36 received >= 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 or 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% confidence interval: 28.2-71.8, n = 22); 1 (3%) patient achieved a radiographic partial response lasting 36 weeks. Four of 34 (12%) patients had prostate-specific antigen reduction of >= 50%. Conclusions: 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.

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Cabazitaxel versus abiraterone or enzalutamide in poor prognosis metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase II trial

M. Annala, S. Fu, J. V. W. Bacon, J. Sipola, N. Iqbal, C. Ferrario, M. Ong, D. Wadhwa, S. J. Hotte, G. Lo, B. Tran, L. A. Wood, J. R. Gingerich, S. A. North, C. J. Pezaro, J. D. Ruether, S. S. Sridhar, H. M. L. Kallio, D. J. Khalaf, A. Wong, K. Beja, E. Schonlau, S. Taavitsainen, M. Nykter, G. Vandekerkhove, A. A. Azad, A. W. Wyatt, K. N. Chi

Summary: This study found that cabazitaxel treatment had a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. The research also indicated that ctDNA abundance is prognostic independent of clinical features, and holds promise as a stratification biomarker.

ANNALS OF ONCOLOGY (2021)