Phase II study of PARP Inhibitor olaparib for women with BRCA 1- or BRCA2-mutated advanced breast cancer

July 11, 2010

Study Design:  Non-randomized, sequential cohort design phase II study
Study Eligibility:  Women aged 18 years or older who had locally advanced breast cancer (not candidates for surgery or radiation) or metastatic breast cancer stage IIIB/IIIC or IV and also with confirmed germline BRCA 1 or BRCA 2 mutation
Enrollment: 27 in the first cohort treated with maximum tolerated dose and 27 in the second cohort treated with 100 mg oral olaparib twice daily 
Research Question:  What is the efficacy and safety of oral olaparib at the maximum tolerated dose (MTD) and at a lower dose in women with BRCA 1 and 2 mutations and advanced breast cancer?

BRCA 1 and BRCA 2 genes are involved in the repair of DNA.  Breast cancer with BRCA 1 or BRCA 2 mutations have defective DNA repair mechanisms and will rely on a protein called poly(ADP-ribose) polymerase (PARP)-1 to carry out DNA repair.  Therefore, a therapy that inhibits PARP-1 may be an effective treatment against cancer by inhibiting the ability of cancer cells to repair their DNA, and thus leading to cell death.  Olaparib (AZD 2281) is a novel, orally active PARP inhibitor.  In the first phase I trial, olaparib at 400 mg twice daily was identified as the maximum tolerated dose (MTD).  In this non-randomized, sequential cohort design phase II trial, investigators assessed the efficacy and safety of oral olaparib in women with BRCA 1and BRCA 2 mutations and advanced breast cancer.  Two cohort groups were given different dosages of olaparib, one group at the MTD and the other group at a lower dose (i.e., 100 mg twice daily).   The primary endpoint was objective response rate (ORR). ORR includes and complete responses, or disappearance of tumors, and partial responses, which include responses with at least a 30% reduction in tumor size.   The secondary endpoints included clinical benefit, defined as the percentage of patients with complete response, partial response, and stable disease for at least 23 weeks, progression-free survival (PFS), and duration of response. 

There was an ORR of 41% (11 of 27 patients) in the cohort or group assigned to the MTD, and an ORR of 22% (6 of 27 patients) in the cohort assigned to 100 mg twice daily.  The clinical benefit rate was 52% for the cohort receiving the MTD and 26% for the cohort receiving the lower dose.  Median PFS was 5.7 months for the cohort receiving the MTD and 3.8 months for the cohort receiving the lower dose.   Adverse events were reported by 44 patients.  Overall, 13 (24%) patients had treatment-associated events that were grade 3 or 4.  Among the cohort receiving the MTD, 11 (41%) of 27 patients had grade 3 or 4 adverse events or changes.  In the cohort receiving the lower dose, 9 (33%) of 27 patients had grade 3 or 4 adverse events. 

This phase II trial tested the safety and efficacy of PARP inhibitor olaparib in women with BRCA 1 and BRCA 2 mutations with advanced metastatic breast cancer.  The trial results showed that when given alone, olaparib may have inferior antitumor activity with a treatment dose of 100 mg twice daily vs. the MTD of 400 mg twice daily.  These results are preliminary and results from a randomized phase III trial with a larger study population will be needed to determine the efficacy of the PARP inhibitor olaparib as an appropriate treatment for women with BRCA 1- or 2-mutated advanced breast cancer.            
 

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