Can Olaparib Improve Outcomes in HRD-High Early Breast Cancer?

A phase II study examining the addition of olaparib to paclitaxel in patients with early breast cancer and homologous recombination deficiency (HRD) failed to meet its primary endpoint regarding pathologic complete response (pCR) rates.

However, the rates found were promising and exceeded that seen in patients who received paclitaxel and carboplatin. Subgroup analyses suggested the most benefit in hormone receptor-positive tumors, younger patients, and those with HRD-high tumors, but no BRCA1 or BRCA2 mutation.

 “The efficacy of olaparib in all breast cancer is not well researched yet,” said Peter A. Fasching, MD, of University Hospital Erlangen in Germany. Fasching presented results of the study at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting, held May 31-June 4 in Chicago.

Previous work suggested there may be a subset of patients with HRD-high tumors that could benefit from olaparib; the new GeparOLA study was a phase II trial that included patients either with an HRD-high score or a somatic or germline BRCA1/2 mutation.       

The study included 102 patients, randomized to receive either paclitaxel plus olaparib (65 patients) or paclitaxel plus carboplatin (37 patients). All patients subsequently received epirubicin and cyclophosphamide, followed by surgery. The study’s primary endpoint was pCR; they aimed to exclude a pCR rate of 55% or lower in the olaparib patients.

The median age in the full cohort was 47.0 years, and 62.3% were pre- or peri-menopausal. All patients had HER2-negative disease, and 27.4% had HR-positive breast cancer. After randomization, 96 patients were found to have HRD-high scores, three had HRD-low scores, and seven were not measurable. A total of 71.7% of patients completed all study treatments.

The primary endpoint was not met; the pCR rate in the olaparib patients was 55.1%, with a 90% confidence interval of 44.5% to 65.3%. Still, this was numerically better than the paclitaxel-carboplatin group, with a pCR rate of 48.6% (90% CI, 34.3–63.2). The study was not designed for a direct comparison between the two arms.

The benefit of olaparib appeared stronger in patients with HR-positive breast cancer, with a pCR rate of 52.6% compared with 20.0% with paclitaxel-carboplatin. In HR-negative patients, the pCR rates in the two groups were 56.0% and 59.3%, respectively.

In patients under 40 years of age, the pCR rate with olaparib was 76.2%, compared with 45.5% with carboplatin. In patients older than that threshold, the pCR rates were 45.8% and 50.0%, respectively.

Finally, olaparib patients with no BRCA mutation had a pCR rate of 51.7%, compared with 37.5% for paclitaxel-carboplatin. In those with BRCA mutations, the rates were 59.0% and 57.1%, respectively.

There were more serious adverse events (AE) reported in the paclitaxel-carboplatin group; 51.3% of those patients had at least one serious AE, compared with 13.0% of those receiving olaparib. There were no fatal AEs in the trial.           

Fasching stressed that the subgroup analyses are only hypothesis-generating at this point, given the small number of patients.

“We think the results are good enough to pursue this treatment option further in the neoadjuvant setting,” he said.

Simon N. Powell, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, discussed the study for ASCO.

“Taxanes are good drugs, but they’re not necessarily selectively targeting homologous recombination defective cancers,” he said, adding that it is possible, given other research, that taxanes such as paclitaxel are not actually the best agents for HR-deficient tumors.

“The subgroup analysis… is certainly very interesting, and we need to understand that more clearly,” he said, noting that it is unclear yet why younger patients and HR-positive patients might fare better with olaparib. “That’s certainly provocative to inquire further.”