One of the best characterized genetic mutations associated with an increased risk of cancers of the breast, ovary, prostate, and others involves the BRCA-genes.
One of the best characterized genetic mutations associated with an increased risk of cancers of the breast, ovary, prostate, and others involves the BRCA-genes. These genes (BRCA-1 and BRCA-2) result in a specific defect in DNA repair mechanisms, making cells predominantly dependent on Poly-adenosine diphosphate ribose polymerase (PARP) for repair. Given the specific defect associated with BRCA-mutations, it has become a target of interest of late.
A class of agents known as PARP inhibitors are now showing great promise. Earlier, I discussed the results of a recent breast cancer trial presented at ASCO utilizing an IV formuation of PARP inhibitors, BSI-201, which when given with chemotherapy for metastatic triple negative breast cancer showed significant activity. Now, a phase I trial of an oral agent, Olaparib (AZD-2281) has been the subject of a recently published phase I study in the New England Journal of Medicine.
In the study by Fong and colleagues, 60 patients with cancer that had progressed despite standard treatment received AZD-2281 at doses ranging from 10mg twice daily for 2-weeks, followed by 1-week rest all the way up to 600mg twice daily every day. At the highest dose level (600mg twice daily) severe thrombocytopenia in one of five patients was noted and somnolence was seen in one of five.
Antitumor activity was only noted in known or suspected (based on family history) BRCA mutation carriers. Of 21 evaluable patients, objective responses were seen in 12 (57%). One patient has had a durable response lasting for over two years.
This paper furthers the promise that personalized medicine can be achieved and the results are very promising. We will definitely be looking for more research coming out on the PARP inhibitor class of agents. Whether there will be a role for these drugs in non-BRCA mutation associated cancers remain to be fully explored but for those whose tumors are associated with BRCA mutations, this study will and should be met with much enthusiasm.
Reference: P.C Fong and Others Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers. NEJM 2009; Abstract published on-line at http://content.nejm.org/cgi/content/abstract/NEJMoa0900212v1.