PARP Inhibitors Play Important Role in Frontline, Recurrent Maintenance Treatment of Ovarian Cancer

With 9 new poly adenosine diphosphate-ribose polymerase (PARP) inhibitor drugs approved for ovarian cancer over the past 6 years, increasing amounts of data are finding that PARP inhibition, both as frontline maintenance and recurrent maintenance, is important for many patients with ovarian cancer.

In a session at the Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer, experts discussed data for olaparib, niraparib, and rucaparib in ovarian cancer. Presenter Bhavana Pothuri, MD, MS, noted that the median progression-free survival (PFS) for patients with ovarian cancer who do not receive maintenance therapy is dismal, with trials finding between 8 and 12 months in control arms. With maintenance therapy, however, trials have found that patients can live progression-free for several years.

In the frontline maintenance therapy setting, PARP inhibition is most effective for patients with high-grade serous ovarian cancer. This is the most common histology in ovarian cancer and is notable for defects in DNA repair, Pothuri said. Furthermore, up to 22% of high-grade serous cancers have BRCA mutations, and 50% overall have defects in homologous recombination.

With this background in mind, Pothuri reviewed notable data from several recent trials.

The SOLO-1 trial investigated frontline olaparib maintenance therapy in patients with FIGO stage 3/4 high-grade serous or endometrioid cancers. Researchers found that 60.4% of patients were progression-free at 3 years in the olaparib arm, compared with 26.9% of patients in the control arm. Pothuri also emphasized the durability of these findings.

“Even after that 2-year treatment cap, that benefit existed,” Pothuri said in her presentation. “At 5 years, almost 50% are still free of disease.”

The PRIMA trial investigated maintenance niraparib versus placebo in patients at high risk after receiving frontline platinum-based chemotherapy. Participants were treated for 3 years or until disease progression, with the primary endpoint of PFS. In this trial, researchers found a 57% reduction in hazard of relapse or death with niraparib, and a hazard ratio of 0.43 in the homologous recombination deficiency (HRD)-positive group. They also found a hazard ratio of 0.62 in the overall population.

Finally, the PAOLA-1 trial investigated maintenance olaparib in combination with bevacizumab in patients with newly diagnosed ovarian cancer. Notably in these data, researchers found a hazard ratio of 0.33 in the group of patients who were HRD-positive with tumor BRCA mutations.

“Overall, PARP inhibitors are well-tolerated and the most common side effects are nausea, fatigue, and myelosuppression,” Pothuri said. “Most of these are really well managed with dose holds [or] dose reductions.”

The American Society of Clinical Oncology guidelines for PARP inhibition in the frontline maintenance therapy setting specifies that niraparib should be offered to all patients with stage 3/4 epithelial ovarian cancer who have had a complete or partial response to platinum-based chemotherapy. Olaparib should be offered to patients with tumor BRCA mutations. Further, clinicians can consider offering olaparib plus bevacizumab to patients with tumor BRCA mutations and/or genetic instability if they have responded to bevacizumab plus chemotherapy.

The second presenter in the session, Floortje J. Backes, MD, discussed data on recurrent maintenance treatment with PARP inhibitors. She focused on data from the SOLO2, ARIEL3, and NOVA trials. All 3 studies enrolled patients with platinum-sensitive, recurrent, high-grade ovarian cancer. PARP inhibitors were started at the completion of platinum-based chemotherapy and continued until progression.

The NOVA trial investigated niraparib 300 mg daily versus placebo. Similar to the frontline data, Backes said the greatest benefits were seen in the group of patients with germline BRCA mutations with a hazard ratio of 0.27. There was also a 50% decreased risk of disease progression in the overall group.

The SOLO2 trial investigated olaparib versus placebo and was the earliest study to have overall survival data. Backes said the treatment benefit continued for patients on olaparib and had a significant benefit, with a profound hazard ratio of 0.03 for PFS.

Finally, the ARIEL3 trial investigated rucapatib 600 mg twice daily versus placebo. It included 3 subgroups: BRCA mutation positive, HRD positive, and intent-to-treat. All 3 groups had similar hazard ratios of 0.21, 0.32, and 0.36, respectively. In the BRCA wild-type setting, researchers found a 0.44 hazard ratio in the loss of heterozygosity (LOH)-high group and a hazard ratio of 0.58 in the LOH-low group.

Like Pothuri, Backes emphasizes that the PFS for all subgroups included in the various control arms was approximately 5.5 months. This highlights the incredible role PARP inhibitors can play in prolonging patients’ PFS times, she said.

Finally, Backes noted that the time to progression on subsequent therapy or death and the time to start of subsequent therapy are improved across all studies. Importantly, she said PARP maintenance does not appear to decrease the efficacy of subsequent therapy.

REFERENCE

Oaknin A, Backes F, Pothuri B. PARP Inhibitors Across the Ovarian Cancer Disease Continuum. Presented at: Society of Gynecologic Oncology 2022 Annual Meeting on Women’s Cancer. March 20, 2022.