A phase Ib/II study testing the safety and efficacy of combined inhibition of the AKT/PI3K and AR signaling pathways in castration-resistant prostate cancer: GDC-0068 or GDC-0980 with abiraterone acetate versus abiraterone acetate.

Abstract

TPS2616 Background: Loss of PTEN, leading to activation of the AKT/PI3K pathway is frequent and associated with poor prognosis in prostate cancer. In addition, AR and AKT/PI3K cross-regulate by reciprocal feedback and combined inhibition of both pathways resulted in improved preclinical efficacy. This study is designed to evaluate the effect of combined inhibition of AR pathway (with abiraterone) and AKT/PI3K pathway (with either GDC-0068 or GDC-0980). GDC-0068 is a potent, selective ATP-competitive inhibitor of AKT1, 2, and 3. Preclinical studies showed that cell and tumor models with PTEN loss are more likely to be sensitive to GDC-0068. GDC-0068 was generally well tolerated in phase I and a MTD of 600 mg daily was identified. GDC-0980 is a potent pan-inhibitor of Class I PI3K and inhibits wild-type and mutated p110α isoforms, as well as mTOR kinase. The recommended phase II dose (RP2D) for single-agent GDC-0980 is 40 mg daily. Methods: This study will enroll CRPC patients previously treated with docetaxel. In phase Ib, the RP2D will be determined separately for GDC-0068 and GDC-0980 in combination with abiraterone 1000 mg qd and prednisone 5mg bid. In phase II, patients will be randomized 1:1:1 to receive GDC-0068 + abiraterone, GDC-0980 + abiraterone, or placebo + abiraterone. The primary endpoint of phase II is PFS measured by PCWG2 in all patients and in patients with PTEN loss. Secondary endpoints include OS, PSA response rate, ORR, safety, Pharmacokinetics and biomarker analyses. The effect of each treatment on the number of circulating tumor cells will be assessed. Primary and secondary analyses will include all randomized patients and will be conducted according to assigned treatment arm. Kaplan-Meier methodology will be used to estimate median PFS for each arm. Up to 24 patients are planned to be enrolled in phase Ib; 240 patients (80 per arm) are planned for phase II. This study is open for accrual; to date 2 patients have been enrolled in phase Ib.