Phase I/Ib study of olaparib and carboplatin in heavily pretreated recurrent high-grade serous ovarian cancer at low genetic risk

// Erika J. Lampert 1 , John L. Hays 2 , Elise C. Kohn 1 , Christina M. Annunziata 1 , Lori Minasian 1 , Minshu Yu 1 , Nicolas Gordon 1 , Tristan M. Sissung 3 , Victoria L. Chiou 1 , William D. Figg 3 , Nicole Houston 1 and Jung-Min Lee 1 1 Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA 2 Ohio State University, Columbus, OH, USA 3 Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA Correspondence to: Jung-Min Lee, email: leej6@mail.nih.gov Keywords: high-grade serous ovarian cancer; BRCA wild type; olaparib; carboplatin Received: February 26, 2019 Accepted: April 04, 2019 Published: April 23, 2019 ABSTRACT Purpose: To investigate maximum tolerated dose (MTD), activity and predictive biomarkers of olaparib with carboplatin in BRCA wild-type ( BRCA wt) high grade serous ovarian carcinoma (HGSOC) patients. Methods: A 3+3 dose escalation study examined olaparib capsules (400 mg twice daily [BID], days 1–7) with carboplatin (AUC3-5 on day 1) every 21 days for 8 cycles, followed by olaparib 400 mg BID maintenance. Blood and tumor biopsy samples were collected pre- and on-treatment in the expansion cohort for PAR levels and proteomic endpoints. Results: 30 patients (median 7 prior regimens [2–12], 63% (19/30) platinum-resistant) were enrolled. Dose-limiting toxicity was thrombocytopenia/neutropenia, and infection with carboplatin AUC5 (2/6 patients). MTD was olaparib 400 mg BID + carboplatin AUC4. Grade 3/4 adverse events (>10%) included neutropenia (23%), thrombocytopenia (20%), and anemia (13%). Five of 25 (20%) evaluable patients had partial response (PR; median 4.5 months [3.3–9.5]). Clinical benefit rate (PR + stable disease ≥4 months) was 64% (16/25). A greater decrease in tissue PAR levels was seen in the clinical benefit group versus no benefit (median normalized linear change −1.84 [−3.39– −0.28] vs 0.51 [−0.27– 1.29], p = 0.001) and a DNA repair score by proteomics did not correlate with response. Conclusions: The olaparib and carboplatin combination is tolerable and has clinical benefit in subsets of heavily pretreated BRCA wt HGSOC, independent of platinum sensitivity.