PARP Combos May Represent Future in Frontline Maintenance Ovarian Cancer Setting

Debra Richardson, MD

Maintenance therapy with olaparib (Lynparza) following chemotherapy is the new standard of care for women with BRCA-mutated ovarian cancer, Debra Richardson, MD, told her audience at the 2019 SGO Winter Meeting.

She added that all women with ovarian cancer should undergo germline testing and BRCA testing at diagnosis. As many as 25% of patients have BRCA1/2 mutations, 18% of which are germline mutations.

However, even with the addition of genomic screenings, the field of gynecologic oncology has an "incomplete understanding" of who will respond to PARP inhibitors, she explained. Patients with BRCA mutations should respond to treatment, but homologous recombination deficiency has been an imperfect biomarker and physicians need more ways of identifying the optimal patient.

“We need to determine the role of a PARP inhibitor after a PARP inhibitor,” said Richardson, a gynecologic oncologist and associate professor with the University of Oklahoma College of Medicine. “Future maintenance may be a PARP inhibitor plus a second agent—and maybe even a third.”

In December 2018, the FDA approved olaparib for maintenance treatment of adult women with deleterious or suspected deleterious germline or somatic BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete response (CR) or partial response (PR) to first-line platinum-based chemotherapy based on results from the phase III SOLO-1 (NCT01844986) trial.

The trial evaluated maintenance olaparib following platinum-based chemotherapy in newly-diagnosed patients with FIGO stage III-IV, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with germline or somatic BRCA1/2 mutation. These patients must have also received cytoreductive surgery.

Patients assigned to 300 mg of daily olaparib for frontline maintenance had significantly improved progression-free survival (PFS). With a median follow-up of 41 months, the median PFS by independent central review was not reached in the olaparib arm (n = 260) versus 14.1 months in the placebo arm (n = 131). The investigator-assessed PFS in the olaparib arm was not reached compared with 13.8 months in the placebo arm (HR, 0.30; 95% CI, 0.23-0.41; P <.0001).

The PFS rate at 36 months also favored olaparib (60% vs 27%).

Investigators are exploring olaparib in the maintenance setting for women with FIGO stage III-IV high-grade serous, epithelial ovarian, fallopian tube, or primary peritoneal cancer in several ongoing studies, including the phase III PAOLA-1 (NCT02477644), PRIMA (NCT02655016), and VELIA (NCT02470585) trials.

Results for PAOLA-1 are expected later this year. In this trial, women who’ve undergone surgery and at least 3 cycles of bevacizumab (Avastin) plus platinum/taxane chemotherapy are randomly assigned to 300 mg daily olaparib plus maintenance bevacizumab or placebo plus bevacizumab maintenance. The primary outcome is PFS1. Secondary outcomes include PFS2, overall survival (OS), and time to first progression.

In PRIMA, women who had CR or PR when treated with a frontline platinum-based regimen will be randomly assigned to 300 mg of daily niraparib (Zejula) or placebo. The primary outcome is PFS1, and secondary outcomes include PFS2, OS, and time to first progression. The primary completion date is February 2020.

VELIA compares veliparib (ABT-888) plus carboplatin/paclitaxel versus placebo in women with stage III-IV high-grade serous ovarian cancer or nonmucinous BRCA-mutation. The combination of PARP plus chemotherapy is unusual, said Richardson. “It's been incredibly difficult to combine PARPs with chemotherapy due to the myelosuppression we see from PARP.”

PARP + Immunotherapy

The primary endpoint is PFS, with OS and disease-related symptom score as the secondary endpoints. The primary completion date is April 2019.PARP inhibitors can enhance DNA damage and mutation load in tumor cells and investigators are looking into ways to combine PARP inhibitors with immunotherapy. An anti-PD—1/PD–L1 agent can then block immunosuppression within the tumor microenvironment and enhance tumor cell death.

Richardson added that preclinical data showed that both a PARP inhibitor and olaparib alone can inhibit tumor growth, but the combination outperformed both single agents.

There are a handful of phase III trials evaluating PARP plus immunotherapy in this patient population including FIRST (NCT03602859), ATHENA (NCT03522246), and JAVELIN Ovarian PARP 100 (NCT03642132).

FIRST is a 3-arm global, randomized, double-blind, controlled trial comparing placebo versus niraparib versus the anti-PD—1 agent TSR-042 followed by maintenance treatment with niraparib and TSR-042. All patients will receive chemotherapy with carboplatin/paclitaxel.

The primary completion date is November 2021.

In ATHENA, a randomized, multinational, double-blind, dual placebo-controlled, 4-arm study, investigators are evaluating rucaparib (Rubraca) and nivolumab (Opdivo) as maintenance treatment in patients who responded to frontline treatment. Primary completion is scheduled for December 2024.

JAVELIN Ovarian PARP 100 is a randomized, open-label, multicenter trial. Investigators will evaluate the efficacy and safety of the anti-PD—L1 monoclonal antibody avelumab (Bavencio) in combination with chemotherapy followed by maintenance therapy with avelumab and the PARP inhibitor talazoparib (Talzenna). Eligible patients must be candidates for bevacizumab in combination with platinum-based chemotherapy.

Investigators hope to show that avelumab plus platinum-based chemotherapy followed by avelumab plus talazoparib maintenance is superior to platinum-based chemotherapy plus bevacizumab followed by bevacizumab maintenance in prolonging PFS. The trial began enrolling patients in July 2018 and has a primary completion date of February 2022.

Richardson D. The future of PARP in the upfront treatment of ovarian cancer. Presented at: the 2019 SGO Annual Winter Meeting; January 17-19, 2019; Lake Tahoe, CA.

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