As PARP inhibitors have now moved into the frontline maintenance setting in ovarian cancer, researchers are now seeking to even further capitalize on use of these agents, including indications in treatment-naïve patients.
Leslie M. Randall, MD, MAS
As PARP inhibitors (PARPi) have now moved into the frontline maintenance setting in ovarian cancer, researchers are now seeking to even further capitalize on use of these agents, including indications in treatment-naïve patients.
PARPi sensitivity is mostly due to germline or somatic BRCA mutations or other mutations leading to homologous recombination repair (HRD) deficiency, Leslie M. Randall, MD, explained at the 37th Annual CFS®.1 Randall, associate professor, director of medical education, and fellowship director in the Division of Gynecologic Oncology at the University of California, Irvine, said that platinum sensitivity may also serve as a marker for the successful use of PARPi.
“PARPi appears to be active across all settings, provided these tumors are high-grade serous endometrioid tumors,” Randall said.
Current indications for PARPi in ovarian cancer include second-line maintenance for patients with recurrent disease, third-line or later treatment for BRCA-mutated tumors, and HRD-positive tumor that are in the fourth-line or later setting following chemotherapy.2-4
Randall said that by looking at the hazard ratios for progression-free survival (PFS) in trials leading to approvals for olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula), it is evident that these agents have significant efficacy in most patients, regardless of BRCA status. “If you look at patients with nonBRCA-mutated tumors, you see significant activity. Not to the degree of those with BRCA mutations, but still significant,” she said.
When approved in the recurrent setting, the question concerning PARPi was whether or not these agents could be effective for frontline indications. The phase III SOLO-1 trial answered this question and served as the basis for which olaparib was approved in the frontline setting as maintenance following platinum-based chemotherapy in women with germline or somatic BRCA-mutated advanced ovarian cancer. Statistically significant improvements in median PFS were observed with olaparib compared with placebo (not reached vs 13.8 months; HR, 0.30; 95% CI, 0.23-0.41; P <.0001).5
According to data from a poster presentation at the 2019 American Society for Clinical Oncology Annual Meeting, olaparib use in SOLO-1 had similar efficacy across prognostic groups, including patients who had upfront surgery (HR, 0.31; 95% CI, 0.21-0.46), interval surgery (HR, 0.37; 95% CI, 0.24-0.58), residual disease following surgery (HR, 0.44; 95% CI, 0.25-0.77), or clinically complete (HR, 0.34; 95% CI, 0.24-0.47) or partial response (HR, 0.31; 95% CI, 0.18-0.52) following chemotherapy.6
“Now, the frontline setting is the exciting playing field for PARP inhibitors. In the frontline setting, we are now where we were a couple of years ago in the platinum-sensitive recurrent maintenance space, showing efficacy for multiple [agents] in multiple settings,” Randall said.
Recently published data from the phase III PRIMA study showed improvement in median PFS with niraparib in the frontline treatment of patients with newly diagnosed disease who responded to platinum-based chemotherapy compared with placebo (13.8 vs 8.2 months; HR, 0.62; 95% CI, 0.50-0.76; P <.001), with even more significant responses observed in patients with HRD-positive disease (21.9 vs 10.4 months; HR, 0.43; 95% CI, 0.31-0.59; P <.001).7
The PARPi veliparib has also produced promising responses in patients with high-grade serous ovarian cancer, when used in combination with carboplatin and paclitaxel followed by veliparib maintenance across all patient subgroups. The median PFS was 23.5 months with veliparib versus 17.3 months in patients treated with placebo (HR, 0.68; 95% CI, 0.56-0.83; P <.001). Similar to other PARPi therapies, the benefit was more significant in patients with BRCA mutations (HR, 0.44; 95% CI, 0.28-0.68; P <.001).8
In the phase III PAOLA-1/ENGOT-ov25 trial, frontline maintenance was improved with the addition of olaparib to bevacizumab (Avastin), with a median PFS of 22.1 months compared with 16.6 months with placebo and bevacizumab in patients with newly diagnosed ovarian cancer following prior treatment with platinum-based chemotherapy (HR, 0.59; 95% CI, 0.49-0.72; P <.0001).9
Managing Toxicities of PARPi
PARPi is generally well tolerated, with adverse events (AEs) most commonly including hematologic events, nausea, vomiting, and fatigue.
“There is evidence to show that some patients do better with a lower starting dose, [such as those] who have a baseline platelet count of <150,000 [/µL] or a baseline weight of <70 kg,” Randall said. “Moft of these AEs happen within the first month and are often managed with dose delay or reduction. If you can get the patient to a steady state within the first month, these AEs generally stabilize and normalize over time.”
Based on evidence from early single-arm trials, there is a black box warning for myelodysplastic syndrome or acute myeloid leukemia for the 3 approved PARPi agents.2-4 The observed incidence of 1% to 2% has been consistently seen over time; however, there has been little difference between the experimental and control arms in placebo-controlled trials, suggesting that these events are not a PARPi class effect.
Randall concluded her presentation by looking to the future of PARPi use, which she says will focus on optimal treatment of HRD-negative patients and overcoming PARPi resistance—an issue almost akin to platinum-resistance—in PARPi combination trials.