PARP Inhibitors Continue to Show Promise in Ovarian Cancer
As PARP inhibitors continue to improve outcomes in patients with ovarian cancer, they may one day be moved into the frontline treatment setting, said Susana M. Campos, M.D., a gynecologic oncologist at Dana-Farber Cancer Institute and an assistant professor at Harvard Medical School.
“It’s important that we start to use these drugs more and more and bring them sooner into the management of the individual,” said Campos, who reviewed trial data and approvals for several PARP inhibitors and looked at the potential for advancing the use of these agents.
Various PARP inhibitors, which interfere with tumor cell ability to make DNA strand repairs, have been approved by the FDA for use following platinum therapy and for maintenance in the ovarian setting. Those include Lynparza (olaparib), for germline BRCA mutations (gBRCAm) following three prior lines of therapy; Rubraca (rucaparib), for gBRCAm and somatic BRCAm following two prior lines; and Zejula (niraparib) and Lynparza for post-platinum maintenance.
Several trials of these agents are important for the light they shed on PARP capabilities, Campos said. Those include NOVA, SOLO-2, STUDY 19 and ARIEL-3.
The NOVA trial applied Zejula in platinum-sensitive, recurrent, high-grade, serous carcinoma, in patients previously treated with at least four cycles of a platinum-containing agent who had shown response, partial or complete. Treatment dosage was 300 mg daily. In the gBRCAm cohort, the median progression-free survival (PFS) for Zejula was 21 months versus 5.5 months on placebo; and in the non-gBRCAm homologous repair defect (HRD)-positive cohort the median PFS was 12.9 and 3.8 months, respectively. In the overall non-gBRCAm group, the median PFS was 9.3 months on Zejula versus 3.9 for placebo.
“Niraparib improved PFS across all three groups—germline and nongermline,” Campos noted.
The SOLO-2 study was unique in that it accrued BRCA1 and BRCA2 mutation carriers only, she said. Patients had at least two prior lines of platinum therapy and had demonstrated sensitivity to platinum. Dosage was 300 mg twice daily. The Lynparza group (196 patients) had a median PFS of 19.1 months versus 5.5 months for those on placebo.
STUDY 19 enrolled patients with platinum-sensitive, high-grade serous ovarian cancer and at least two previous platinum regimens. Of 265 recruited, 22 percent were BRCA positive and 14 percent were BRCA negative. The rest were BRCA wild-type. Lynparza dosage was 400 mg orally, twice daily. Treatment was until disease progression. In the primary analysis, median PFS was 8.4 months for Lynparza and 4.8 months on placebo. Campos noted that what was particularly significant about this study was that it accepted all comers, whether they were BRCA carriers or not.
The ARIEL3 study was a phase 3 randomized trial of Rubraca versus placebo in patients with ovarian cancer who had responded to platinum therapy. In the BRCAm subgroup, median PFS was 16.6 months for Rubraca and 5.4 months on placebo; for patients in the HRD BRCA germline or somatic group, the median PFS was 13.6 versus 5.4 months; and in a third group that included germline or somatic BRCAm plus BRCA wild-type, the median PFS was 10.8 months for patients on Rubraca versus 5.4 months for those on placebo.
Although the trials produced striking efficacy data, “It’s also important to balance [treatment decisions] with knowledge of toxicity, and in truth all PARP inhibitors share some common toxicities in terms of gastrointestinal toxicities as well as hematological adverse events [AEs],” Campos said . Common AEs included anemia, neutropenia, and thrombocytopenia. “Thrombocytopenia was seen a bit frequently in the NOVA trial very early on, but it was clearly attenuated with a dose reduction, so that is quite important.”
“There are other toxicities that can be unique to one or two particular agents, and as you tailor these drugs to your patients, knowing these toxicities is extremely important.” Metabolic effects and drug-to-drug interactions are also important to understand, she noted.
“We want these drugs in the upfront setting,” and the question is whether past and ongoing trial activity will provide the necessary evidence for doing so, Campos said. In addition, there are other riddles that need to be solved, such as the workings of mechanisms of resistance to PARP inhibitors and whether PARP inhibitors can be used after PARP inhibitors. “The elephant in the room is how can testing strategies for BRCAm or non-BRCAm ovarian cancer be used to personalize treatment strategies?” she said.
Nevertheless, there’s enough ongoing trial activity to guarantee that some answers will emerge. “We often think of patients we could have given these drugs to many years ago and didn’t have them to give. It’s a very exciting time in the management of ovarian cancer,” Campos concluded.