A Phase I, Open-Label, Dose-Finding Study of GSK2636771, a PI3Kβ Inhibitor, Administered with Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer - Expert Commentary

Deletions of PTEN are common in metastatic CRPC, particularly as early driver events, and lead to constitutive activation of PI3K/AKT/mTOR signaling pathways. Such activation not only readily feeds forward to drive cellular proliferation and survival, but, in prostate cancer specifically, can permit evasion of AR-targeted therapies. Consequently, the authors completed a phase I study to evaluate safety and preliminary activity in the rescue of sensitivity to enzalutamide, a potent AR inhibitor, by the addition of an inhibitor of PI3Kβ (GSK2636771) specifically in mCRPC tumors deficient in PTEN (via IHC).

The population (n = 36 receiving at least one dose) was heavily pretreated and all with prior progressive disease on (and without interruption longer than 30 days in) enzalutamide. Most men had received prior surgery and radiotherapy; a third of men had received prior abiraterone and a quarter had received prior chemotherapy. Importantly, most men enrolled had previously responded to enzalutamide, supporting the plausibility of re-sensitizing a tumor. Two phases (first dose-escalation via modified 3+3, second dose-expansion) were completed, ultimately determining 300 mg of the study agent to be the MTD, in combination with full-dose enzalutamide (160 mg daily). The authors concluded that the combination was favorable with regard to safety and tolerability with most patients not needing dose reduction or interruption. The most common adverse events (AEs) were diarrhea, decreased appetite, and fatigue (all greater than 30%). Treatment-related AEs of grade 3 or higher were observed in 31% of subjects, most commonly hypertension and fatigue.

Antitumor activity was limited, with a 12-week non-progressive disease rate of 50% (95% CI 28.2-71.8, n=22) with 4 of 34 (12%) of subjects demonstrating a PSA50 or better. A single RECIST partial response was observed. Although perhaps not as active as hoped, this combination was deployed in a heavily pre-treated population and the authors suggest that earlier deployment (perhaps prior to resistance to AR signaling inhibitors) could forestall the development of resistance. Additionally, the pursuit of correlative analyses, such as pre- and on-treatment biopsies of tissue or circulating compartment could provide insight into mechanisms of progression and sensitivity, including analysis of signaling outputs downstream of PI3K. Perhaps such analysis could refine the sensitive population beyond PTEN deficiency.

Written by: Jones Nauseef, MD, PhD, Assistant Professor of Medicine, Division of Hematology and Medical Oncology at Weill Cornell Medicine, and Assistant Attending physician at NewYork-Presbyterian Hospital

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