PARP Inhibitors Intriguing Despite Research Setbacks

Michael J. Birrer, MD, PhD

Professor of Medicine Harvard Medical School Director, Gynecologic Medical Oncology Director, Gynecologic Cancer Research Program Massachusetts General Hospital Cancer Center Boston, MA

Early excitement over the potential for using PARP inhibitors in the treatment of patients with ovarian cancer has dissipated amid disappointing findings on overall survival, but the class of novel therapeutics remains under active investigation for patients with this tumor type.

At least three pharmaceutical companies are continuing development programs with various PARP agents, noted Michael J. Birrer, MD, PhD, in a recent interview. He spoke shortly after AstraZeneca announced its decision to halt studies of olaparib for maintenance treatment of serous ovarian cancer.

“I haven’t given up hope on this,” said Birrer, referring to the class of PARP inhibitors as a whole. “I think you’ll see trials with PARP inhibitors testing the ability and activity of bringing the PARP inhibitor up front in newly diagnosed patients in combination with chemotherapy. Most of those trials will also include a maintenance phase. In conjunction with that, there will be selective trials in BRCA1- and BRCA2- mutated patients with recurrent resistant disease.”

PARP, poly(adenosine diphosphate [ADP]—ribose) polymerase, plays an important role in the repair of single-strand DNA breaks. Birrer said single-strand breaks can become double-strand breaks that are, in turn, repaired by a complex that contains BRCA1 and BRCA2. Thus, he said, researchers have theorized that inhibiting the PARP enzyme should selectively kill cells with those genetic abnormalities.

Earlier studies had demonstrated higher antitumor activity and objective response rates for patients with and without BRCA1/2 mutations, a phase II trial highlighted at the 2011 American Society of Clinical Oncology Annual Meeting in June did not require that mutation status. Eligible patients had recurrent, platinum-sensitive ovarian or fallopian-tube cancer or primary peritoneal cancer with high-grade (grade 2 or 3) serous features or a serous component.

The trial, which AstraZeneca sponsored, demonstrated that olaparib improved median progression-free survival by 65% among the 136 patients randomized to receive 400-mg doses twice daily, compared with 129 participants on placebo. Investigators believed the compound showed promise as monotherapy for this patient population.

In December, however, AstraZeneca announced the company would not move forward with phase III development in the maintenance setting after interim data “indicated that the previously reported progression-free survival benefit is unlikely to translate into an overall survival benefit, the definitive measure of patient benefit in ovarian cancer. In addition, attempts to identify a suitable tablet dose for use in phase III studies have not been successful.”

In March, researchers detailed those results in The New England Journal of Medicine. They reported median progression-free survival of 8.4 months with olaparib versus 4.8 months on placebo. Adverse events were more prevalent among those who received olaparib, but most of those events were grade 1/2, with nausea, fatigue, vomiting, and anemia among the most frequently reported effects.

Stage IIC Cancer

This illustration depicts ovarian cancer at stage IIC. One noteworthy PARP study included patients with grade 2 or 3 serous ovarian cancer.

However, the interim survival analysis, conducted after 38% of the participants had died, did not show a significant advantage for olaparib, which demonstrated a hazard ratio of 0.94 (95% confidence interval, 0.63-1.39; P = 0.75).

“Maintenance treatment with olaparib was associated with a significant improvement in progression-free survival among patients with platinum-sensitive, relapsed, high-grade serous ovarian cancer,” the researchers concluded. “However, at the interim analysis, this did not translate into an overall survival benefit. As of this writing, 21% of the patients were still receiving olaparib (and 3% were still receiving placebo), which indicates that the disease is controlled for a prolonged period in some patients.”

Birrer said the trial results presented at ASCO were “remarkable,” but that the FDA would want to see an overall survival advantage before approving a new drug. He said there also remains “a fair amount of confusion” about what would be the best dosage for patients, with studies evaluating doses ranging from 100 mg to 400 mg twice daily.

Meanwhile, companies that are continuing to study PARP inhibitors in ovarian cancer include Abbott Laboratories, which is studying veliparib (ABT-888) as monotherapy for patients with relapsed ovarian cancer with a BRCA mutation; Clovis Oncology, which is exploring rucaparib (CO-338) in BRCA-associated ovarian cancer; and BioMarin Pharmaceutical Inc, which is investigating BMN-673 in patients with advanced or recurrent solid tumors, including ovarian cancers.

Key Research

Ledermann JA, Harter P, Gourley C, et al. Phase II randomized placebocontrolled study of olaparib (AZD2281) in patients with platinumsensitive relapsed serous ovarian cancer. J Clin Oncol. 2011;29(suppl; abstr 5003).

Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer [published online ahead of print March 27, 2012]. N Engl J Med. doi: 10.1056/NEJMoa1105535.