Olaparib improved response in BRCA-mutated breast, ovarian cancers

New findings from two small, multicenter, international, phase 2 studies indicated that higher dose olaparib, an oral poly (ADP-ribose) polymerase inhibitor, may be an effective therapy with minimal adverse effects in women with ovarian and breast cancers who carry BRCA1 and BRCA2 gene mutations.

The findings, some of which were originally presented at the 2009 ASCO Annual Meeting, were published this week in The Lancet.

About 10% of women with ovarian cancer and up to 5% of women with breast cancer carry the BRCA1 and – BRCA2 genes, which increase the risk for breast and ovarian cancers. Until now, knowledge of a BRCA mutation has not affected the selection of treatment for ovarian or breast cancer.

In cancer models with BRCA1 or BRCA2 mutation, blockade of poly(ADP-ribose) polymerase (PARP), which is important to repair single-strand DNA breaks, synthetically kills the mutated cancer cells. The combination of two repair defects induces killing of the cells. These findings indicate that olaparib, which kills BRCA-deficient cells, might be useful as a cancer treatment in patients with these mutations.

For this reason, researchers conducted two studies to assess the safety and efficacy of olaparib therapy in women aged 18 years or older with advanced ovarian (n=57) and breast cancers (n=34) who are also carriers of BRCA1 and BRCA2 gene mutations.

In both studies, researchers observed better treatment response with olaparib 400 mg twice daily vs. olaparib 100 mg twice daily. For the ovarian cancer study, patients assigned the higher dose of olaparib had an objective response rate (ORR) of 33% compared with 13% of patients assigned to lower-dose therapy. Conversely, patients in the breast cancer study assigned higher-dose olaparib had an ORR of 41% compared with 22% of those assigned to lower-dose olaparib.

“This is the first time that we have been able to take the genetic reason a person has developed cancer and make it a target,” Susan M. Domchek, MD, associate professor of medicine at the University of Pennsylvania School of Medicine, said in a press release. “It is a strategy that may cause fewer side effects for patients.”

Ovarian cancer study

In the first study, conducted by M. William Audeh, MD, of the Samuel Oschin Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, and colleagues, women with confirmed BRCA1 and -BRCA2 gene mutations and recurrent, measurable ovarian cancer were assigned either olaparib 400 mg (n=33) or olaparib 100 mg twice daily (n=24). Primary outcome measures for both studies was objective response rate; women in both studies were previously assigned a median of three prior chemotherapy regimens.

Compared with an objective response rate of 13% in women assigned olaparib 100 mg twice daily, women assigned olaparib 400 mg twice-daily had an objective response rate of 33%.

The most frequently observed adverse events for those assigned the higher dose of olaparib were nausea (grade 1 or 2, 42%; grade 3 or 4, 6%); fatigue (grade 1 or 2, 30%; grade 3 or 4, 3%); and anemia (grade 1 or 2, 15%; grade 3 or 4, 3%). The most common adverse events in women assigned 100 mg twice-daily were nausea (grade 1 or 2, 29%; grade 3 or 4, 8%) and fatigue (grade 1 or 2, 38%).

Breast cancer study

In the second study, women with confirmed BRCA1 and BRCA2 gene mutations and recurrent, advanced breast cancer were also assigned either olaparib 400 mg (n=27) or olaparib 100 mg twice daily (n=27).

Compared with an objective response rate of 22% in women assigned olaparib 100 mg twice daily, women assigned olaparib 400 mg twice daily had an objective response rate of 41%.

Although mainly low grade, the most frequently observed adverse events for those assigned higher dose olaparib were fatigue (grade 1 or 2, 41%; grade 3 or 4, 15%); nausea (grade 1 or 2, 41%; grade 3 or 4, 15%); vomiting (grade 1 or 2, 11%; grade 3 or 4 11%); and anemia (grade 1 or 2, 4%; grade 3 or 4, 11%). The most common adverse events in women assigned lower dose olaparib were nausea (grade 1 or 2, 41%) and fatigue (grade 1 or 2, 26%; grade 3 or 4, 4%).

Although findings from both studies have been positive thus far, researchers recommend for further research to be conducted before olaparib and other oral PARP inhibitors become available for regular use.

“It is important for patients to join these clinical trials because we need to determine how best to use these drugs, on their own or in combination with other agents,” Domchek said. “And we need to establish definitively that they are better than other drugs.” – by Jennifer Southall

There are important proof-of-principle trials demonstrating the utility of marker/pathophysiology-driven clinical trials. The fact that there were notable responses to single-agent olaparib, along with very reasonable tolerability profile in many of these patients, paves the way for larger trials and hopefully, the required studies to warrant regulatory agency approval. At the same time, not all patients responded, and the responses seen were mainly partial. These data highlight the fact that both breast and ovarian cancers are heterogeneous and that multiagent therapies will continue to be needed, at least for the foreseeable future. For now, PARP inhibition is a very promising strategy, worthy of strong support from the translational and patient community.

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

Audeh MW. Lancet. 2010; doi:10.1016/S0140-6736(10)60893-8.

Tutt A. Lancet. 2010; doi:10.1016/S0140-6736(10)60892-6.

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