Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-sensitive epithelial ovarian cancer (cohort A).

person Fiona Simpkins Penn Medicine Abramson Cancer Center, Philadelphia, PA info_outline Fiona Simpkins, Dimitrios Nasioudis, Stephanie L. Wethington, Lainie P. Martin, Janos Laszlo Tanyi, Nawar A. Latif, Drew A. Torigian, Dalia K. Omran, Diego Rodriguez, Simon Smith, Emma Dean, Susan M. Domchek, Ronny Drapkin, Ie-Ming Shih, Eric J Brown, Wei-Ting Hwang, Deborah Kay Armstrong, Stephanie Gaillard, Robert Lawrence Giuntoli, Joyce F. Liu

Authors person Fiona Simpkins Penn Medicine Abramson Cancer Center, Philadelphia, PA info_outline Fiona Simpkins, Dimitrios Nasioudis, Stephanie L. Wethington, Lainie P. Martin, Janos Laszlo Tanyi, Nawar A. Latif, Drew A. Torigian, Dalia K. Omran, Diego Rodriguez, Simon Smith, Emma Dean, Susan M. Domchek, Ronny Drapkin, Ie-Ming Shih, Eric J Brown, Wei-Ting Hwang, Deborah Kay Armstrong, Stephanie Gaillard, Robert Lawrence Giuntoli, Joyce F. Liu Organizations Penn Medicine Abramson Cancer Center, Philadelphia, PA, Johns Hopkins University School of Medicine, Baltimore, MD, Department of Radiology, University of Pennsylvania, Philadelphia, PA, AstraZeneca, R&D Oncology, Royston, United Kingdom, AstraZeneca, R&D Oncology, Cambridge, United Kingdom, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, Department of Cancer Biology and the Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, Dana-Farber Cancer Institute, Boston, MA Abstract Disclosures Research Funding NIH 5R37CA215436–02 SPORE 1P50CA228991, V Foundation, AstraZeneca #827744, Basser Center Background: Currently there are no alternatives to chemotherapy for patients (pts) with platinum-sensitive recurrent high-grade serous ovarian cancer (PSOC). Preclinical data have demonstrated strong synergy between poly (ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) regardless of homologous recombination deficiency (HRD) status. We present results of an investigator-initiated study examining the combination of PAPRi and ATRi in patients (pts) with PSOC. Methods: Pts with PSOC and measurable disease by RECIST v1.1 were enrolled (NCT03462342). Prior PARPi was permitted but not mandatory and there was no limit to number of prior regimens. Pts received ceralasertib (C) 160mg po once daily, days 1–7 and olaparib (O) 300mg po twice daily, on days 1–28 of a 28-day cycle until unacceptable toxicity or disease progression. Primary end points were efficacy based on objective response rate (ORR) and toxicity. Secondary endpoint was progression-free survival (PFS). Myriad MyChoice CDx and Caris Life Sciences MI Profile assays were used to determine presence of tumor genomic instability; HRD (positive if score >42) or loss of heterozygosity (LOH) (positive if 38% of tested genomic segments exhibited LOH). Results: Thirty-seven pts were enrolled and evaluable for toxicity; 33 pts were available for response evaluation. Median number of prior regimens was 1 (range 1-3) while 2 pts received prior PARPi. Germline homologous recombination (HR) gene mutations were present in 3 (8.1%) pts (1 BRCA2, 1 BRIP1, 1 RAD51C),10 (27%) pts had tumors exhibiting genomic instability (8 with HRD positive and 2 with LOH high), while 19 (51.4%) pts had tumors without genomic instability, and 5 (13.5%) pts had unknown status. Pts received a median of 8 cycles (range 1-50). Fifteen (40.5%) pts experienced a grade (G) 3 toxicity event, most commonly anemia 21.6% (n=8) and diarrhea 5.4% (n=2). Two pts (5.4%) had G4 thrombocytopenia. Dose reductions occurred in 14 pts (37.8%); one pt discontinued treatment due to toxicity (G2 fatigue and nausea). ORR was 48.5% with 3 complete responses (CR) and 13 partial responses (PR) and median progression-free survival (mPFS) was 8.3 months (95% CI: 5.9, 10.7). ORR and mPFS in 16 pts with tumors without genomic instability was 43.8% (1 CR, 6 PR) and 7.6 months (95% CI: 5.4, 9.8). ORR in 10 pts with tumors with genomic instability was 40% (4 PR) with a mPFS of 8.3 months (95% CI: 5.1, 11.5). ORR in 3 pts with germline HR gene alterations was 100% (1 CR, 2 PR) with mPFS not reached. ORR in 4 pts with unknown status of genomic instability was 50% (1CR, 1PR). Conclusions: C+O was well tolerated and active in pts with platinum sensitive HGSOC warranting further evaluation. Efficacy was seen regardless of the presence of tumor genomic instability. Clinical trial information: NCT03462342.

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