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]

Neither regimen is optimal in that relapse remains the norm. It may be inappropriate to expect that any single regimen can be an effective therapy for all patients with advanced ovarian cancer. Both cisplatin and carboplatin are likely to have a role in future treatment strategies.