Combination of PARP and ATR inhibitors (olaparib and ceralasertib) shows clinical activity in acquired PARP inhibitor-resistant recurrent ovarian cancer

Abstract

Background: Following multiple blockbuster studies demonstrating long-term progression free and overall survival benefits with poly(ADP-ribose)polymerase inhibitors (PARPi), they have become an integral component of high grade serous ovarian cancer (HGSOC) treatment. Unfortunately, tumors ultimately acquire resistance and thus therapies that overcome PARPi-resistance are urgently needed. Preclinical studies show the addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARPi overcome PARPi-resistance. We present results of an investigator-initiated study of the combination PARPi (olaparib) and ATRi (ceralasertib) in patients who were on a PARPi and experienced disease progression. Methods: We conducted a non-randomized trial (NCT03462342) in platinum sensitive HGSOC immediately following prior PARPi treatment of a 28 day cycle of olaparib 300mg orally twice daily and ceralasertib 160mg orally once daily on days 1-7. Eligibility required a germline or somatic BRCA1/2 mutation, other homologous recombination deficient (HRD) mutation, or positive HRD score (>42 on Myriad My Choice). Clinical benefit from prior PARPi was required ( > 12 months on treatment for 1st line maintenance, > 6 months for ≥2nd line maintenance, or treatment of recurrence with response by CA-125 or imaging). No intervening treatment between the PARPi and enrollment was permitted. The primary objectives were safety and objective response rate (ORR). Results: Thirteen patients (pt) of median age 60 years (range 43-78) were enrolled. 9 pt (69%) had germline BRCA mutations, 3 (23%) somatic BRCA mutations and 1 (8%) a positive HRD score. Median time on prior PARPi was 13 months (range 4-60). Prior PARPi indication was 1st line maintenance in 8% (n = 1), 2nd line maintenance in 38% (n = 5) and recurrence in 54% (n = 7). Nine pt (69%) had received olaparib prior to enrollment. The time from prior PARPi to cycle 1, day 1 was 34 days (range 22-311). The ORR was 46% (n = 6); all 6 demonstrating a PR. Pt received a median of 8 (range 3-23) cycles of olaparib and ceralasertib. 4 pt remain on study (4-14 months). 4 pt (31%) experienced grade 3 toxicity: 23% (n = 3) thrombocytopenia, 16% (n = 2) anemia, and 16% (n = 2) neutropenia. There were no grade 4/5 toxicities. There were 4 dose reductions (3 olaparib, 1 ceralasertib). No pt discontinued treatment due to toxicity. Conclusions: The combination of olaparib and ceralasertib is well tolerated and shows clinical activity in in a cohort of patients with recurrent HRD HGSOC who have progressed on prior PARPi thus warranting further investigation. This study is the first to suggest the potential of ATR inhibitors to overcome PARPi resistance in an HRD patient population. Molecular profiling studies are underway to identify potential biomarkers associated with response to guide future clinical trial design.