TY - JOUR
T1 - A phase I, open-label, dose-finding study of GSK2636771, a PI3Kb inhibitor, administered with enzalutamide in patients with metastatic castration-resistant prostate cancer
AU - Sarker, Debashis
AU - Dawson, Nancy A.
AU - Aparicio, Ana M.
AU - Dorff, Tanya B.
AU - Pantuck, Allan J.
AU - Vaishampayan, Ulka N.
AU - Henson, Lynn
AU - Vasist, Lakshmi
AU - Roy-Ghanta, Sumita
AU - Gorczyca, Michele
AU - York, Whitney
AU - Ganji, Gopinath
AU - Tolson, Jerry
AU - de Bono, Johann S.
N1 - Funding Information:
D. Sarker reports personal fees and non-financial support from Ipsen, Bayer, and Eisai; personal fees from AstraZeneca, Surface Oncology, MSD, and AAA; grants from Inspirata, Roche, and UCB; and nonfinancial support from MINA Therapeutics outside the submitted work. T.B. Dorff reports personal fees from Bayer, BMS,
Publisher Copyright:
2021 American Association for Cancer Research
PY - 2021/10/1
Y1 - 2021/10/1
N2 - 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 PI3Kb inhibitor GSK2636771 at 300 mg initial dose, with escalation or deescalation 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 ¼ 22; 300 mg: n ¼ 12; 400 mg: n ¼ 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n ¼ 1; 300 mg: n ¼ 2, 400 mg: n ¼ 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 ¼ 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.
AB - 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 PI3Kb inhibitor GSK2636771 at 300 mg initial dose, with escalation or deescalation 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 ¼ 22; 300 mg: n ¼ 12; 400 mg: n ¼ 2) plus 160 mg enzalutamide. Dose-limiting toxicities occurred in 5 patients (200 mg: n ¼ 1; 300 mg: n ¼ 2, 400 mg: n ¼ 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 ¼ 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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U2 - 10.1158/1078-0432.CCR-21-1115
DO - 10.1158/1078-0432.CCR-21-1115
M3 - Article
C2 - 34281912
AN - SCOPUS:85117831465
SN - 1078-0432
VL - 27
SP - 5248
EP - 5257
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -