Women with newly diagnosed advanced ovarian cancer that has responded to first-line platinum-based chemotherapy should be offered poly (ADP-ribose) polymerase (PARP) inhibitor maintenance therapy. In addition, treatment with PARP inhibitor monotherapy should be offered to patients with recurrent ovarian cancer who have not already received a PARP inhibitor and whose tumor demonstrates genomic instability.
These are among the recommendations from newly released guidelines on the use of PARP inhibitors in the management of ovarian cancer from the American Society of Clinical Oncology (ASCO).
The guidelines are based on a systematic review of the literature, and were developed by a multidisciplinary Expert Panel, which included 2 patient representatives and an ASCO guidelines staff member with health research methodology expertise. The research scope encompassed 17 clinical trials, US Food and Drug Administration (FDA) approvals, and pertains to patients who are PARP inhibitor–naïve.
“Recent studies have confirmed that the efficacy of PARP inhibitors is enhanced not only in germline/somatic BRCA ovarian cancer but also in cancers in which homologous recombination deficiency (HRD) is caused by other underlying etiologies. The applications of PARP inhibitors in the management of ovarian cancer are complex and all approvals to date are predicated on the absence of previous exposure to PARP inhibitors,” wrote William P. Tew, MD, Medical Oncologist, Gynecologic Cancer and Clinical Trials, Memorial Sloan Kettering Cancer Center, New York City, and colleagues.
The guidelines cite insufficient evidence to support the use of PARP inhibitors in initial treatment of early-stage (stage I-II) ovarian cancer, instead recommending their use as maintenance for women with newly diagnosed stage III-IV ovarian cancer.
PARP inhibitor monotherapy maintenance in the second-line or after may be offered to patients with stage III-IV ovarian cancer who have not already received a PARP inhibitor and who have responded to platinum-based therapy regardless of BRCA mutation status, the guidelines state. In this setting, treatment is continued until progression of disease or toxicity despite dose reductions and best supportive care. PARP inhibitor options are olaparib (Lynparza) 300 mg every 12 hours, rucaparib (Rubraca) 600 mg every 12 hours, and niraparib (Zejula) 200 to 300 mg once daily. The quality of the evidence supporting this strong recommendation is rated as high.
Olaparib is recommended for those women with germline or somatic pathogenic or likely pathogenic variants in BRCA1 and BRCA2 genes, whereas niraparib is recommended in all women with a response to first-line platinum-based chemotherapy for the treatment of high-grade serous or endometrioid ovarian cancer. Duration of maintenance is 2 years for olaparib and 3 years for niraparib but “longer duration could be considered in selected individuals.”
In maintenance therapy for the second-line or greater setting, Study 19, SOLO2, NOVA, and ARIEL3 clinical trials all demonstrated significant improvement in progression-free survival (PFS) with PARP inhibitor treatment compared with placebo.
“Across all studies, women with a germline/somatic BRCA mutation had the most robust clinical improvements,” the guidelines panel wrote. SOLO2 also showed an improvement in overall survival by approximately 13 months (hazard ratio, 0.74; P = .054) compared with placebo.
According to the guidelines, “Adding olaparib to bevacizumab (Avastin) maintenance may be offered to patients who have stage III-IV high-grade serous, or endometrioid ovarian cancer and germline, or somatic pathogenic or likely pathogenic variants in BRCA1 or BRCA2 genes and/or genomic instability, and who have achieved a partial or complete response to chemotherapy plus bevacizumab combination.”
The management of recurrent disease was also addressed. In this setting, the guidelines state that a PARP inhibitor should be offered to patients with recurrent ovarian cancer who have not already received a PARP inhibitor and have BRCA1 or BRCA2 germline somatic pathogenic or likely pathogenic variants. Treatment options in this setting are olaparib 300 mg every 12 hours, rucaparib 600 mg every 12 hours, and niraparib 200 to 300 mg once daily. The evidence quality supporting this determination is high, and the recommendation is rated as strong.
In the setting of recurrent disease in patients with BRCA mutations, PARP inhibitor monotherapy is recommended, with Study 42, SOLO3, Study 10, ARIEL2, and QUADRA clinical trials all reporting a significant improvement in response and PFS with a PARP inhibitor, evidence quality that rates as high, and a strength of recommendation that is strong.
Olaparib is FDA approved for “the treatment of patients with germline BRCA-mutated ovarian cancer who have received ≥3 previous lines of chemotherapy, and rucaparib is approved for the treatment of patients with germline BRCA-mutated ovarian cancer who have received ≥2 chemotherapy regimens,” the guidelines state.
The guidelines apply to women who are PARP inhibitor–naïve, the authors emphasized. Retreatment with a PARP inhibitor is not advised at this time and is “an important area of unmet need for investigation,” they wrote.
PARP inhibitors are not recommended for use in combination with chemotherapy, other targeted agents, or immune-oncology agents outside the context of a clinical trial.
The guidelines suggest management strategies for specific toxicities, mainly hematologic, associated with PARP inhibitors. Anemia, neutropenia, thrombocytopenia (most commonly with niraparib), and persistent cytopenia are hematologic toxicities mentioned specifically. Dose reduction or dose hold is recommended, with the strength of this recommendation rated as moderate. Persistent thrombocytopenia warrants discontinuation of the PARP inhibitor while evaluation for treatment-related myelodysplastic syndrome/acute myeloid leukemia is suggested for patients with persistent cytopenia despite drug hold. Nausea is another common side effect that may necessitate dose reduction if persistent and/or severe.