Phase II trial of the PI3 kinase inhibitor BKM120 with or without enzalutamide in men with metastatic castration resistant prostate cancer (mCRPC).

Abstract

5025 Background: PI3K pathway activation is common in mCRPC. BKM120 (buparlisib) is an oral, pan-class I PI3 kinase inhibitor. Preclinical data demonstrated a reciprocal feedback loop between PI3K and androgen receptor (AR) signaling; thus, we evaluated the efficacy of BKM120 in men with heavily pre-treated mCRPC including those progressing on enzalutamide (E). Methods: This was a 3 site phase 2 Dept of Defense Prostate Cancer Clinical Trials Consortium open-label trial of BKM120 100 mg once daily with ongoing ADT in men with mCRPC who had failed or were not candidates for docetaxel. Continuation of E was permitted in men progressing on E with subsequent addition of BKM120. The primary endpoint was the rate of composite of radiographic and clinical PFS at 6 months with a goal of 40% vs. a historic rate 25% using a two-stage design with interim futility analysis. Results: Thirty men were accrued: 63% post-docetaxel; median PSA was 70 ng/dl, 83% had > 4 prior therapies for CRPC; 43% men received concurrent E. The trial met criteria for futility, with a 6 month PFS rate of 10% (95% CI 2.5-23.6%). Median composite PFS was 1.9 months (95% CI: 1.8, 3.4) and 3.5 months (95% CI 1.2, 5.5) with concurrent E. Median OS was 11 months (95% CI 4.8, 14.4). E did not appear to increase the BKM120 side effect profile. The PSA decline proportion was 23%, but no patients achieved a > 50% decline, with median PSA change of +39%. No objective responses were observed. Related SAEs occurred in 3 men including respiratory infection and organ failure (1), urinary tract obstruction due to local progression (1), and severe confusion (1). One seizure was observed in a man who was found to have a new CNS metastasis during concurrent BKM120/E therapy. Grade 3 related AEs were seen in 47% of patients, with 10% stopping BKM120 due to toxicity. The most common related AEs included grade 1-2 weight loss, diarrhea, nausea, fatigue, anorexia, rash, hyperglycemia, and anxiety and mood disorders. Conclusions: BKM120 did not improve PFS over historic control data in men with mCRPC, either alone or when added to AR inhibition in men progressing on enzalutamide. These data suggest that PI3K inhibition is not sufficient to block mCRPC progression. Clinical trial information: NCT01385293.