Phase II trial of the oral PARP inhibitor olaparib (AZD2281) in BRCA-deficient advanced ovarian cancer

Abstract

5500 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 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 chemotherapy-refractory ovarian cancer. The secondary aim was to assess the safety and tolerability profile in ovarian cancer patients with BRCA1/2 deficiency. Methods: In an international, multicenter, proof-of-concept, single-arm, phase II study, two patient (pt) sequential cohorts received continuous oral olaparib in 28-day cycles, initially at the MTD, 400 mg bd (33 pts), and subsequently at 100 mg bd (24 pts), a previously shown clinically active and PARP inhibitory dose. Eligibility criteria included confirmed genetic BRCA1/2 mutation and recurrent, measurable, incurable disease (previous chemotherapy, median 3 lines). The primary efficacy endpoint was best objective response rate (ORR; RECIST) post baseline. Change in CA125 was a secondary efficacy endpoint. All adverse events were reported using CTCAE v3. Results: At this interim analysis dated October 31, 2008, of 57 enrolled pts (39 BRCA1 deficient and 18 BRCA2 deficient), 33 were evaluable at 400 mg bd and 24 at 100 mg bd. The confirmed RECIST ORR was 33% at 400 mg bd and 12.5% at 100 mg bd. Clinical benefit rate (ORR and/or confirmed >50% decline in CA125) was 57.6% at 400 mg bd and 16.7% at 100 mg bd. Toxicity was mainly mild in severity, reflecting grade 1/2 nausea (44%); fatigue (35%); and anemia (14%). Grade 3 toxicity occurred infrequently, and comprised primarily nausea (7%) and leukopenia (5%). Conclusions: Oral olaparib is well tolerated and highly active in advanced, chemotherapy-refractory BRCA-deficient ovarian cancer, with greater activity seen at the higher dose. Toxicity in BRCA1/2 carriers was similar to that seen in non-carriers. This study provides positive proof of the concept of the activity and tolerability of genetically defined targeted therapy with olaparib in BRCA-deficient ovarian cancers. [Table: see text]

A Current Review of Targeted Therapeutics for Ovarian Cancer

“…Recently reported were the results of a phase II trial of the oral PARP inhibitor Olaparib (AZD 2281) in BRCA-deficient advanced ovarian cancer [ 86 ]. An international, phase II study examined two cohorts of patients that received oral olaparib in 28-day cycles, initially at the MTD, 400 mg bid (33 pts), and subsequently at 100 mg bid (24 pts).…”

PARP inhibitors in BRCA1/BRCA2 germline mutation carriers with ovarian and breast cancer

“…The therapy was well tolerated, and investigators reported a 41% overall response rate in the patients of the first cohort, with a median progression-free survival of 5.7 months. The second clinical trial tested the same two sequential dose cohorts in women with BRCA-deficient advanced ovarian cancer [ 10 ]. At the time of the preliminary report, 33 patients were treated at the 400 mg dose, with response in 57.6% of patients and a median progression-free survival of 5.8 months.…”

Targeted Therapies in Epithelial Ovarian Cancer

“…Multiple PARP inhibitors are currently being examined in phase II trials. Of interest, Audeh et al lately reported the interim analysis of a phase II study employing Olaparib in BRCA-deficient advanced ovarian cancer [ 57 ]. Overall 57% of patients demonstrated response to PARP inhibition, using either RECIST or CA-125 criteria.…”