Olaparib inhibited PARP in BRCA1/2 cancers

Olaparib, a poly (ADP-ribose) polymerase inhibitor, successfully inhibited PARP and demonstrated antitumor activity with few adverse effects in cancers with BRCA 1/2 mutations, according to the findings from a phase-1 trial.

Although this is a small, early-stage trial, the findings are important and “[point] to a new direction in the development of anticancer drugs,” J. Dirk Iglehart, MD, director, and Daniel P. Silver, MD, PhD, instructor, at Dana-Faber Cancer Institute, Harvard Medical School, wrote in an accompanying editorial.

Researchers enrolled 60 patients — 22 with BRCA 1 or 2 mutations — to examine the pharmacokinetic and pharmacodynamic characteristics of olaparib. In this cohort, olaparib was assigned on a dose-escalating schedule from 10 mg once a day for two of three weeks up to 600 mg twice daily continuously.

During the first cycle, dose-limiting toxicity was observed in three patients. One patient assigned to 400 mg twice a day exhibited grade-3 mood alteration and fatigue. A patient assigned to 600 mg twice a day exhibited grade-4 thrombocytyopenia, and another patient assigned to 600 mg twice a day exhibited grade-3 somnolence.

Despite this, most adverse effects were grade-1 or -2 including nausea, fatigue, vomiting, taste alteration and anorexia and a low incidence of myelosuppresion.

Researchers then enrolled a second cohort consisting solely of BRCA1/2 carriers; they were assigned olaparib 200 mg twice a day. There was no observed increase in the frequency or grade of adverse effects among carriers of BRCA1/2.

Pharmacokinetic analysis of olaparib indicated rapid absorption with the peak plasma concentration observed between one and three hours after administration. The terminal-elimination half-life was approximately five to seven hours.

Compared with baseline, inhibition of PARP was >90% in cells of patients assigned to ≥60 mg of olaparib twice a day.

Antitumor activity was observed in BRCA1/2 carriers with ovarian, breast or prostate cancer with the exception of one patient, with a family history of BRCA mutation, who declined mutational testing.

A phase-2 study of PARP inhibition in patients with advanced breast cancer and BRCA 1/2 mutations was presented earlier this year at ASCO.

This was an important trial, in which approximately one-third of patients had tumors with specific molecular abnormalities. Although not curative, this study demonstrated significant antitumor responses only noted in patients with BRCA 1/2 mutations with minimal toxicity. Overall, this a proof of principle trial, as it reinforces not only that oral agents can be effective, but also, and perhaps more importantly, it opens the possibility for a new era of effective, targeted approaches for patients whose tumors have abnormalities of DNA repair mechanisms. We in the medical field should be encouraged by the evolution of this research and should support further trials to help determine potential regulatory agency approval.

– Edith A. Perez, MD
HemOnc Today Editorial Board member

Fong PC. N Engl J Med. 2009;doi:10.1056/NEJMoa0900212.