Abstract A72: Combination ATR and PARP inhibitor (CAPRI) for recurrent, platinum-resistant ovarian cancer
Authors: Payal D. Shah, Haley Zarrin, Stephanie Wethington, Nawar Latif, Lainie Martin, Diego Rodriguez, Katie Elkins, Robert Giuntoli, Robert Burger, Janos Tanyi, Mark Morgan, Susan M. Domchek, Stephanie Gailliard, Deborah K. Armstrong, Fiona Simpkins
Journal: Clinical Cancer Research (2020)

Abstract Background: Platinum-resistant (PR) ovarian cancer (OC) is a lethal disease for which effective therapies are limited. Preclinical data suggest that inhibitors of poly(ADP-ribose) polymerase (PARP) and ataxia telangiectasia and Rad3-related kinase (ATR) have synergistic antitumor activity in these tumors. We hypothesize that targeting two unique DNA repair pathways with combination therapy may increase response rates, durability of response, and lower off-target toxicities compared to standard treatments. This clinical trial examines PARP and ATR inhibition (PARPi-ATRi) in patients (pts) with recurrent OC (NCT03462342). Data from the PR arm of this trial are presented. Methods: Twelve patients were enrolled with PROC in the first stage of a Simon optimal two-stage design with alpha=0.10 and beta=0.10. Eligible pts had recurrent, PR high-grade serous OC, measurable disease, and no prior treatment with a targeted inhibitor of DNA repair. Pts may or may not have a somatic or germline mutation of BRCA1 or BRCA2. Pts received olaparib (O) 300mg orally twice daily on days 1-28 and AZD6738 (A) 160mg orally daily on days 1-7 of a 28-day cycle. Endpoints were safety (toxicity based on CTCAE v5.0), objective response rate (RECIST v1.1), and PFS (RECIST v1.1). If ≥1 patient of 12 treated has a partial or complete response, then 25 additional patients will be treated; if no responses are seen, the PR arm of this trial will be terminated. Results: Nine patients have been treated and 8 pts have had on-study imaging thus far. Median (M) age is 63 years (53-73); M ECOG, 0 (0-1); M prior lines of chemotherapy, 2.5 (1-4); M prior therapies after acquiring platinum resistance, 0.5 (0-2). BRCA1/2m status (positive/negative/unknown) is: gBRCA1 (1/5/4); gBRCA2 (0/6/4); sBRCA1 (1/7/2); sBRCA2 (0/8/2). No complete or partial responses were seen. Six of 8 patients achieved SD with a mean duration on study of 6.7 cycles (range 4-10 cycles), including 1 pt with gBRCA1m. Three of these 6 pts demonstrated 20-27% tumor regression of target lesions. Two patients had disease progression. Toxicities occurring in ≥50% of pts that were at least possibly related to combination therapy were nausea (grade (G) 1/2: 6, G3: 1); anorexia (G1/2: 5, G3: 1); fatigue (G1/2: 4, G3: 1), anemia (G1/2: 4, G3: 1). No G4 toxicities were observed and no pts discontinued therapy due to toxicity. Conclusions: Combination O and A is tolerable with mostly low-grade toxicity similar to that of olaparib single-agent. 75% of response-evaluable pts had stable disease, half of whom had substantial tumor regression. Duration of disease stability was clinically meaningful in this PR, largely g/sBRCA1/2 wild-type OC population. Biopsy samples will be evaluated by genomics and proteomics. Updated response data will be presented. Citation Format: Payal D. Shah, Haley Zarrin, Stephanie Wethington, Nawar Latif, Lainie Martin, Diego Rodriguez, Katie Elkins, Robert Giuntoli, Robert Burger, Janos Tanyi, Mark Morgan, Susan M. Domchek, Stephanie Gailliard, Deborah K. Armstrong, Fiona Simpkins. Combination ATR and PARP inhibitor (CAPRI) for recurrent, platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A72.