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PARPis for Ovarian Cancer
Contemporary Use of PARP Inhibitors in Advanced Ovarian Cancer

Released: July 12, 2023

Stephanie Shuey
Stephanie Shuey, PharmD, BCOP
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Key Takeaways
  • It is essential to assess genetic and tumor biomarkers to identify optimal treatment options for patients with advanced ovarian cancer, particularly maintenance therapy with PARP inhibitors.
  • Olaparib with or without bevacizumab, niraparib, and rucaparib are all guideline-recommended options for frontline maintenance therapy in advanced ovarian cancer.
  • Single-agent PARP inhibitors are no longer recommended as treatment for heavily pretreated patients with advanced ovarian cancer.

All patients with advanced ovarian cancer who experience a partial or complete response to frontline platinum-based chemotherapy are candidates for PARP inhibitor maintenance therapy. The choice of agent is guided by biomarkers. Each agent has slightly different FDA approvals and guideline-endorsed indications. Frontline therapy typically has been followed by either maintenance therapy or observation. Although most patients will respond to frontline treatment, relapse frequently occurs in advanced-stage disease within 3 years. At the time of relapse, patients can again receive chemotherapy, potentially followed by maintenance therapy depending on genetic and tumor testing, as well as what they received for frontline treatment.

Biomarkers are important in determining treatment options for patients with ovarian cancer, particularly maintenance therapy. Germline and somatic alterations that lead to homologous recombination deficiency (HRD) are predictive of response to PARP inhibitors. HRD status is defined as either mutations in homologous recombination repair genes such as BRCA1/2 or genomic instability, which is caused by other genetic or epigenetic alterations that lead to error-prone DNA repair. Because genomic alterations are common and influence treatment decisions, leading oncology societies recommend testing for all patients with ovarian cancer. All patients with newly diagnosed disease should undergo genetic testing for mutations in BRCA1/2 and other ovarian cancer susceptibility genes. If germline testing is negative, patients should then undergo somatic tumor testing for BRCA1/2 and likely pathogenic variants. If the patient is found to not have any BRCA mutations, HRD testing should be considered. In the recurrent setting, more comprehensive tumor molecular testing should be considered.

PARP Inhibitors as Frontline Maintenance Therapy

The 3 PARP inhibitors used for frontline maintenance in advanced ovarian cancer are olaparib, niraparib, and rucaparib. Olaparib was approved by the FDA with or without bevacizumab in patients with pathogenic or likely pathogenic variants in BRCA1/2. Patients with BRCA wild-type but HRD-positive tumors as determined by the companion diagnostic test are also candidates for olaparib, but only in combination with bevacizumab. In 2020, niraparib was approved by the FDA for frontline maintenance in all patients irrespective of biomarkers based on findings from the PRIMA study. Rucaparib currently is not approved by the FDA for frontline maintenance therapy, but in 2022, several guidelines were updated to include it as an option for all patients irrespective of biomarkers based on findings from the ATHENA-MONO trial. 

The data supporting PARP inhibitors as frontline maintenance therapy are from 4 phase III trials: SOLO1 for olaparib, PRIMA for niraparib, PAOLA-1 for olaparib plus bevacizumab, and ATHENA-MONO for rucaparib. All of these trials included patients with advanced-stage disease who had experienced a response to first-line platinum-based chemotherapy. PARP inhibitor maintenance had the greatest magnitude of benefit in patients with BRCA mutations across all 4 trials, resulting in a 60% to 70% improvement in progression-free survival (PFS) compared with placebo. In the past year, long-term efficacy data have been published from SOLO1, PRIMA, and the PAOLA-1 trials. In SOLO1, olaparib improved PFS by approximately 3.5 years compared with placebo at the 5-year follow up, which was statistically significant. We saw similar results in the 3.5-year follow-up from PRIMA, in which niraparib significantly improved PFS regardless of tumor HRD status. The 5-year follow-up from the PAOLA-1 trial showed an overall survival (OS) benefit with the combination of olaparib and bevacizumab, which was statistically significant in the BRCA-mutated and BRCA wild-type HRD-positive populations. 

PARP Inhibitors as Maintenance Therapy Following Therapy for Recurrence

In patients with platinum-sensitive disease who respond to therapy, maintenance therapy with a PARP inhibitor again can be considered. Multiple guideline recommendations for PARP inhibitors in ovarian cancer currently state that maintenance PARP inhibitor therapy following recurrence therapy should be considered only in patients who have not previously received a PARP inhibitor because of the lack of data for retreatment with PARP inhibitors. Olaparib is approved by the FDA for maintenance treatment of platinum-sensitive recurrent disease irrespective of biomarkers. However, niraparib and rucaparib are restricted to use in patients with BRCA mutations—specifically germline BRCA mutations for niraparib. 

PARP Inhibitors No Longer Recommended for Treatment of Recurrence

Previously, all 3 PARP inhibitors were indicated for the treatment of recurrent ovarian cancer following several prior lines of therapy in specific populations. In 2022, approval of rucaparib for treatment of BRCA-mutated ovarian cancer was withdrawn based on the ARIEL4 trial, which showed decreased OS with rucaparib compared with chemotherapy. Subsequently, approval of olaparib for treatment of germline BRCA-mutated recurrent ovarian cancer was withdrawn based on SOLO3, which showed an almost 10-month decrease in OS in patients who had received 3 or more prior lines of therapy. Finally, approval of niraparib for treatment of recurrent platinum-sensitive ovarian cancer was voluntarily withdrawn based on the totality of evidence from the SOLO3 and ARIEL4 trials.

Areas of Investigation

Because PARP inhibitors are effective as maintenance treatment, primarily as monotherapy, there is interest in combining them with other targeted agents such as antiangiogenics, immune checkpoint inhibitors, or cell cycle kinase inhibitors (with targets including ATR and Wee1) to increase efficacy and overcome resistance, particularly in the setting of relapsed disease. There is preliminary evidence of activity with some PARP inhibitors in combination with other targeted therapies in recurrent ovarian cancer. However, further research is required to determine which populations are most likely to benefit. Are they more effective in platinum-sensitive vs platinum-resistant disease, and what is the role of biomarkers in predicting response? We also need more phase III randomized trials comparing these regimens with standard-of-care chemotherapy to determine their place in therapy. Finally, trials are ongoing to determine the role of PARP inhibitors in combination with immunotherapy and bevacizumab for first-line maintenance of ovarian cancer. If these combinations are found to be efficacious, this could affect the place in therapy of PARP inhibitors and subsequent lines of treatment. Additional trials of repeating PARP inhibitor therapy in patients who have previously been exposed in earlier lines of therapy suggest that PARP inhibitor rechallenge may be beneficial for both maintenance therapy and treatment of recurrent disease.

In summary, leading oncology societies recommend genetic testing for BRCA1/2 mutations and HRD for all patients with ovarian cancer, as genetic and tumor molecular alterations are common and affect treatment decisions. Pharmacists involved in the care of patients with ovarian cancer can optimize outcomes for those with advanced ovarian cancer by keeping up to date with the rapidly evolving data about place in therapy for PARP inhibitors and educating their patients about the nuances of frontline and maintenance therapies. 

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