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Updated: Oct 27, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in
Debashis Sarker1, Nancy A Dawson2, Ana M Aparicio3
1King's College London and Guy's Hospital, London, United Kingdom.
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 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, 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.
Insights
Dual targeting of androgen receptor (AR) and PI3K/AKT pathways with enzalutamide and GSK2636771 showed acceptable safety in metastatic castration-resistant prostate cancer (mCRPC). However, limited antitumor activity was observed in patients with PTEN-deficient mCRPC who progressed on enzalutamide.
Area of Science:
- Oncology
- Pharmacology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) often develops resistance to androgen receptor (AR)-targeted therapies like enzalutamide.
- PTEN inactivation activates PI3K/AKT signaling, contributing to treatment resistance and poor outcomes in prostate cancer.
Purpose of the Study:
- To evaluate the safety, tolerability, and efficacy of combining enzalutamide with a PI3Kβ inhibitor (GSK2636771) in patients with PTEN-deficient mCRPC who have progressed on enzalutamide.
- To determine the recommended phase II dose for this combination therapy.
Main Methods:
- A phase I clinical trial (NCT02215096) enrolled patients with PTEN-deficient mCRPC previously treated with enzalutamide.
- Patients received escalating doses of GSK2636771 (300 mg initial dose, with 100 mg increments) plus a fixed dose of enzalutamide (160 mg).
- Primary objectives included safety assessment, dose determination, and evaluation of the 12-week non-progressive disease (PD) rate.
Main Results:
- 37 patients were enrolled; 36 received at least one dose of the combination therapy.
- Dose-limiting toxicities were observed in 5 patients (20%). No new or unexpected adverse events were reported.
- At the recommended dose (GSK2636771 200 mg + enzalutamide 160 mg), the 12-week non-PD rate was 50%. One patient had a partial response, and 12% achieved a ≥50% prostate-specific antigen reduction.
Conclusions:
- The combination of GSK2636771 and enzalutamide demonstrated acceptable safety and tolerability in patients with PTEN-deficient mCRPC.
- Limited overall antitumor activity was observed, suggesting further investigation or combination strategies may be needed for this patient population.
