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]

PARP Inhibitors: An Interesting Pathway also for Non-Small Cell Lung Cancer?

“…Such study was conducted in 54 patients (27 treated with olaparib 400 mg bid, 27 at the dose of 100 mg bid) with an objective response rate (ORR) of 41% and 22% respectively. PFS was 5.7 months in the cohort with 400 mg bid and 3.8 in the cohort with 100mg bid [31,32]. A good tolerability of the treatment was reported with grade 3 or higher toxicities seen in 5 patients in terms of fatigue, nausea and anemia.…”

Combining Emerging Agents in Advanced Breast Cancer

“…In a phase II trial of heavily pretreated patients with recurrent, measurable, chemotherapy-refractory BRCA mutation-associated breast cancer, the PARP inhibitor olaparib (400 mg twice daily and subsequently 100 mg twice daily) demonstrated measurable single-agent efficacy, with an ORR as high as 41% [60]. Like BRCA-associated breast cancers, triple-negative breast cancer is sensitive to PARP inhibition in the presence of platinum-based chemotherapy.…”

Hereditary breast cancer and genetic counseling in young women

“…There is also a study that has demonstrated the therapeutic efficacy of treatment in advanced breast cancer. In a phase II trial, the efficacy of the oral poly (ADP-ribose) polymerase inhibitor olaparib in BRCA-deficient advanced breast cancer was evidenced [21].…”