Phase II trial of the oral PARP inhibitor olaparib in BRCA-deficient advanced breast cancer

Abstract

CRA501 Background: Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. A phase I trial identified 400 mg bd as the maximum tolerated dose (MTD) with an initial signal of efficacy in BRCA-deficient ovarian cancers (ASCO 2008; abst 5510). The primary aim of this study was to test the efficacy of olaparib in confirmed BRCA1/BRCA2 carriers with advanced refractory breast cancer. The secondary aim was to assess safety and tolerability in this population. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two sequential patient (pt) cohorts received continuous oral olaparib in 28-day cycles initially at the MTD, 400 mg bd (27 pts), and subsequently at 100 mg bd, a previously identified PARP inhibitory dose (27 pts). Eligibility criteria included confirmed BRCA1/BRCA2 mutation and recurrent, measurable chemotherapy-refractory breast cancer. The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Progression-free survival (PFS) and clinical benefit rate were secondary endpoints. All adverse events were reported using CTCAE v3. Results: On November 20, 2008, 54 pts exposed to a median of three prior lines of chemotherapy had been enrolled. 27 pts were dosed at 400 mg bd (18 BRCA1 deficient and 9 BRCA2 deficient), and 24 of these had databased RECIST assessments. The ORR (currently based on unconfirmed responses) was 38% (9/24) (400 mg bd). Causally-related toxicity was mainly mild (grade 1–2) in severity; 9/27 pts (33%) had fatigue; 7/27 (26%) had nausea; 4/27 (15%) had vomiting; and 1/27 (4%) had anemia. Causally-related grade 3 or higher toxicities were seen in 5 pts (19%) with fatigue (3 pts), nausea (2 pts), and anemia (1 pt). 27 pts were treated in the subsequent 100 mg bd cohort where no data are currently available. Conclusions: Olaparib at 400 mg bd is well tolerated and highly active in advanced chemotherapy-refractory BRCA-deficient breast cancer. Toxicity in BRCA1/BRCA2 carriers was similar to that reported previously in non-carriers. This first study with olaparib in BRCA-deficient breast cancers provides positive proof of concept for high activity and tolerability of a genetically defined targeted therapy. [Table: see text]