2011 SGO News: PARP Inhibitor Active in Ovarian Cancer

Almost half of patients with heavily pretreated ovarian cancer benefited from an investigational PARP inhibitor, results of a phase I study showed.

Of 39 evaluable patients, 10 had partial responses and eight others had stable disease for a minimum of 12 weeks. The two groups combined had a clinical benefit rate of 46%, as reported at the Society of Gynecologic Oncology meeting.

“Antitumor activity was observed in heavily pretreated BRCA1 and BRCA2 mutation carriers, and preliminary antitumor activity was seen in patients with sporadic cancers,” said Robert Wenham, MD, of the H. Lee Moffitt Cancer Center in Tampa, Fla.

PARP (poly ADP ribose polymerase) is essential to base excision repair in cancer cells, including repair of chemotherapy-induced damage. Inhibition of PARP has a strong biologic rationale, and multiple clinical trials to date have demonstrated promising clinical activity for several different members of the PARP inhibitor class.

Developed in an oral formulation, MK-4827 selectively inhibits PARP 1 and 2 to disrupt the repair of single-strand DNA excision breaks.

The agent induces cell death in tumors that have homologous recombination-repair deficiency, including tumors with BRCA1/2 loss and in tumor cell lines with homologous recombination defects unrelated to BRCA1/2. The broad spectrum of activity has provided support for clinical application of MK-4827 in sporadic cancers.

Wenham reported data from the first-in-human trial of MK-4827, involving patients with various types of advanced solid tumors. The report focused on patients with heavily pretreated ovarian cancer, accrued in a two-step enrollment process.  The primary objectives of the study were safety and tolerability, identification of dose-limiting toxicities and maximum tolerated dose, and determination of the dose for phase II evaluation.

Secondary objectives included evaluation of the pharmacokinetic and pharmacodynamic profiles of MK-4827 and preliminary assessment of the agent in patients with cancers likely to have homologous recombination DNA repair defects.

Investigators enrolled 60 patients in the first phase of the trial and 20 in the second phase, more than half (47 of 80) of whom had advanced ovarian cancer.

The maximum tolerated dose proved to be 300 mg. Pharmacodynamic studies confirmed PARP inhibition at MK-4827 doses of 80 mg and greater.

Of the 39 patients included in the efficacy assessment, 15 had unknown BRCA status, five were BRCA negative, and 19 were BRCA positive.

Wenham reported that 11 patients with BRCA-positive tumors (58%) derived benefit from treatment with MK-4827 — four patients achieved stable disease and seven had partial responses.

Seven patients with BRCA-unknown status (47%) had clinical benefit, four with stable disease and three with partial responses. None of the small group of BRCA-negative patients had stable disease or partial responses.

Several patients had progression-free survival (PFS) lasting a year or more, including one who had a partial response and associated PFS of more than 500 days and another whose PFS fell just short of 500 days.

The results add to the encouraging activity PARP inhibitors have demonstrated in ovarian cancer from the beginning of clinical evaluation almost five years ago, said invited discussant William Audeh, MD, of Cedars-Sinai Medical Center in Los Angeles.

“Although patient response was not a primary endpoint of this study, the responses and clinical benefit are quite impressive,” said Audeh.  “It’s clear that PARP inhibitors have activity as single agents in ovarian cancer,” he added.

The challenge will be to identify biomarkers that will allow for selection of patients who are most likely to benefit from treatment, Audeh continued. As shown in the data Wenham and others have reported, BRCA mutations confer sensitivity to PARP inhibitors.

Wenham agreed that BRCA mutations identify candidates for PARP inhibitors, but he suggested that several biomarkers could prove to be predictive. Ultimately, an assay consisting of a panel of biomarkers might be required to identify candidates for the therapy.