Phase I expansion of olaparib (PARP inhibitor) and AZD5363 (AKT inhibitor) in recurrent ovarian, endometrial and triple negative breast cancer

Abstract

Background: We sought to confirm the recommended phase II dose (RP2D) of the combination of olaparib and AZD5363 in women's cancers and evaluate molecular markers of response and resistance. Methods: Olaparib tablet formulation (O) was given orally BID, AZD5363 (A) was given orally on a 4 day on/3 day off schedule. Two dose levels were planned per the ComPAKT study (Yap AACR 2015). Responses were defined using RECIST 1.1. Patients had biopsies at baseline and after 28 days of treatment for planned correlative testing. Results: To date, 38 patients (pts) have been enrolled. Median number of prior therapies was 4 (1-8). Only 7 (18%, 5 ovarian, 2 breast) pts had known germline BRCA mutation. The first two pts on DL1 (O 300mg; A 400mg) experienced DLTs of diarrhea and vomiting. Therefore, 6 pts were treated on DL-1 (O 300mg; A 320mg). There were no DLTs on DL-1, therefore, 6 additional pts were treated on DL1. There were no DLTs on re-explored DL1. DL1 was confirmed as the RP2D. Expansion phase was performed with an additional 24 pts. Most common adverse events (≥15%) were anemia (89%, G3/4 16%), nausea (76%, G3/4 5%), diarrhea (74%, G3/4 5%), leukopenia (61%, G3/4 11%), elevated creatinine (58%, G3/4 3%), hyperglycemia (42%, G3/4 0%), fatigue (42%, G3/4 0%), vomiting (39%, G3/4 5%), anorexia (32%, G3/4 0%), mucositis (26%, G3/4 0%), hypertriglyceridemia (18%, G3/4 0%), thrombocytopenia (18%, G3/4 0%), neutropenia (18%, G3/4 10%), hypercholesterolemia (18%, G3/4 0%), hyponatremia (16%, G3/4 5%) and constipation (16%, G3/4 0%). Of 30 pts evaluable for response, overall response rate (RR) was 24%. Seven had confirmed partial response including 1 ovarian, 4 endometrial and 2 triple negative breast cancer pts. RR among endometrial cancer pts was 50% (4/8). Six additional pts had stable disease for greater than 4 months including 4 ovarian and 1 endometrial cancer pts. Assessment of molecular correlatives of response and resistance are ongoing. Conclusions: The combination of olaparib tablet formulation and AZD5363 is well tolerated at the confirmed RP2D and demonstrates preliminary evidence of durable tumor activity in ovarian, endometrial and triple negative breast cancer. Promising response was seen in the endometrial cancer cohort.