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Olaparib for Cancers Associated with BRCA Mutations

The poly(adenosine diphosphate ribose) polymerase inhibitor olaparib showed antitumor activity in patients with BRCA1- and BRCA2-associated malignancies.

BRCA mutations cause tumor cells to lose the ability to repair double-strand DNA breaks by homologous recombination. However, this loss of function can be compensated for in such cancer cells by base-excision repair, which is mediated by the enzyme poly(adenosine diphosphate ribose) polymerase (PARP). Would inhibiting PARP be an effective cancer treatment in BRCA-mutation carriers?

To test this strategy, investigators in the U.K. and the Netherlands conducted an industry-supported, phase I trial of the oral PARP inhibitor olaparib. The trial involved 60 patients (with melanomas or breast, ovarian, prostate, or colorectal tumors), 23 of whom carried BRCA1 or BRCA2 mutations. All patients had previously received 1 treatment regimen; most (53%) had received 4 regimens. Olaparib dosing was initiated at 10 mg daily and increased to 600 mg twice daily, given continuously in 4-week cycles.

Durable antitumor activity (assessed at baseline and during the first and second treatment cycles) was observed only in BRCA mutation carriers: Of 19 evaluable BRCA-positive patients who had BRCA-related tumors, 12 (63%) achieved clinical responses or disease stabilization (for 4 months), and 9 (47%) achieved responses based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria. All dosing schedules were well tolerated; however, twice-daily 400-mg and 600-mg regimens were associated with relatively high incidence of fatigue, nausea, vomiting, and dizziness.

Comment: The authors conclude that olaparib has antitumor activity in BRCA1- and BRCA2-associated cancers and is well tolerated. Recent studies have shown that PARP inhibitors are active against BRCA-associated malignancies, either as single agents or in combination with cytotoxic drugs (JW Oncol Hematol Jun 16 2009 and J Clin Oncol 2008; 26:3785). PARP inhibitors are emerging as a best strategy for combating tumors that are associated with BRCA mutations. Further experience with these promising agents is eagerly awaited.

— Virginia Kaklamani, MD, DSc

Dr. Kaklamani is an Assistant Professor in the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine in Chicago.

Published in Journal Watch Oncology and Hematology August 4, 2009

Citation(s):

Fong PC et al. Inhibition of poly(ADP-Ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009 Jul 9; 361:123.

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Iglehart JD and Silver DP. Synthetic lethality — A new direction in cancer-drug development. N Engl J Med 2009 Jul 9; 361:189.

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