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Ovarian PARP Inhibitors
My Thoughts on the Evolving Landscape of PARP Inhibitors and the Role of Biomarkers in Ovarian Cancer

Released: November 02, 2021

Expiration: November 01, 2022

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In this commentary, Nicoletta Colombo, MD, shares her thoughts on the latest clinical evidence for improved outcomes with PARP inhibition in ovarian cancer. After an overview of key trials, the discussion focuses on the use of BRCA mutations and homologous recombination deficiency (HRD) status as biomarkers to guide treatment and on the increasingly important role of bevacizumab in this setting.

The Evolving Landscape of PARP Inhibition in Ovarian Cancer
Multiple phase III trials continue to advance the role of PARP inhibitors in ovarian cancer, most prominently SOLO1 (frontline olaparib), PRIMA (niraparib in higher-risk patients), PAOLA-1 (olaparib plus bevacizumab), and VELIA (veliparib plus chemotherapy). Each trial met its primary endpoint of progression-free survival (PFS), and subsequently olaparib, niraparib, and olaparib/bevacizumab all were approved as frontline maintenance therapy in ovarian cancer by the FDA and European Medicines Agency (EMA) .

SOLO1 assessed olaparib vs placebo as maintenance therapy in patients with newly diagnosed ovarian cancer and a germline or somatic BRCA mutation following a response to first-line platinum-based chemotherapy (N = 391). In total, 391 patients were randomized 2:1 to receive either olaparib or placebo for up to 2 years if there was no evidence of disease. Patients with a partial response were allowed to continue treatment beyond 2 years. The primary endpoint was investigator-assessed PFS. Long-term follow-up data from SOLO1 were presented at the European Society for Medical Oncology Virtual Congress 2020. In patients who received 2 years of olaparib following standard treatment, 48.0% had not progressed vs 20.5% in the placebo arm after 5 years of follow-up. Women who received olaparib had a median PFS of 56 months vs 14 months with standard treatment only. Previously, PARP inhibitors had primarily been evaluated in relapsed disease, whereas these first-line data demonstrate substantial benefit earlier in the disease course.

PRIMA is a double‑blind phase III study that randomized 733 women with advanced and high-risk serous ovarian cancer 2:1 to maintenance therapy with niraparib or placebo following first-line platinum-based chemotherapy. All enrolled women had achieved at least a partial response to the chemotherapy and had stage III with residual tumor after primary debulking surgery or undergoing neoadjuvant chemotherapy (65%) or stage IV (35%) ovarian cancer. Initial results presented in 2019 showed benefit for niraparib maintenance across biomarker subgroups compared with placebo. At the 2020 Society of Gynecologic Oncology Annual Meeting, Monk and colleagues presented updated data from an exploratory analysis of PRIMA showing that niraparib improved PFS in both HRD (BRCA mutated and wild type) and homologous recombination proficient (HRP) ovarian cancer. The benefit was greatest in patients with HRD ovarian cancer, with an HR of 0.43 vs 0.68 in patients with HRP ovarian cancer. Of importance, the treatment effect was consistent in patients with BRCA1 and BRCA2 mutations. Based on results from the PRIMA study, niraparib was approved by the FDA and EMA in 2020 for maintenance treatment of patients with advanced ovarian cancer and a response to first-line platinum-based chemotherapy.

PAOLA-1 was a randomized phase III trial evaluating the addition of olaparib to bevacizumab as maintenance therapy in patients with newly diagnosed, FIGO stage III-IV, high-grade serous/endometrioid ovarian, fallopian tube, or primary peritoneal cancer (N = 806). Initial results showed that the combination of olaparib and bevacizumab improved PFS beyond bevacizumab alone (HR: 0.59). At the International Gynecologic Cancer Society 2020 Annual Global Meeting, Harter and colleagues presented data from an exploratory analysis in higher-risk vs lower-risk patients enrolled on PAOLA-1. Results showed significantly superior PFS in both groups with the combination, particularly those patients with HRD or a BRCA mutation. At 2 years, 90% of lower-risk patients receiving the combination remained progression free vs 56% of higher-risk patients receiving the combination. By contrast, 2-year PFS in the bevacizumab plus placebo groups was 43% for lower-risk patients and 23% for higher-risk patients. Based on findings from PAOLA-1, recent approvals include the combination of olaparib and bevacizumab, approved in 2020 by both the FDA and the EMA as maintenance therapy for patients who responded to platinum-based chemotherapy and have HRD.

Biomarkers in Ovarian Cancer
HRD is frequently seen in high-grade ovarian cancer and is associated with sensitivity to PARP inhibition. Approximately 13% of all high-grade serous ovarian cancer is associated with germline mutations in BRCA1/2; these inactivating mutations impair the ability of homologous recombination to repair double-strand DNA breaks. As such, genetic testing for BRCA1/2 mutations is recommended for all patients with ovarian cancer or women who are at risk for ovarian cancer (eg, family history of ovarian cancer or known inherited BRCA1/2 mutations).

The value of this was highlighted at the 2021 International Gynecologic Cancer Society meeting in a presentation by Sims and colleagues on a retrospective analysis of clinical and survival outcomes in patients with high-grade ovarian cancer, stratified by HRD status, who were receiving frontline and/or maintenance therapy. Results showed that in patients with germline BRCA-mutation, somatic BRCA/HRD-positive, high-grade ovarian cancer, PFS and overall survival with PARP inhibitor maintenance were superior to patients with wild-type BRCA or who were HRP.

There are 2 main testing strategies for HRD. One is to test for specific mutations within BRCA1/2 (or other homologous recombination repair HRR genes) by examining a panel of genes or just a single gene. There are thousands of documented mutations in BRCA1 and BRCA2, so identifying them is not straightforward. Another strategy is to test for the phenotypic effects of HRD within the tumor genome (ie, loss of heterozygosity). Other techniques to determine whether HRD is present include looking for telomeric allelic imbalance (caused by reciprocal translocations) and chromosomal rearrangements such as large chromosomal breaks. Identifying these features can identify HRD-positive tumors without needing to identify specific gene mutations.

A genomic instability test has been developed that can identify loss of heterozygosity and other HRD phenotypes and includes BRCA1/2 mutations. This test is being used to select patients with ovarian cancer for PARP inhibitor therapy. Of note, as seen in results from PAOLA-1 presented at the 2021 Society of Gynecologic Oncology meeting, the detection of mutations in non-BRCA HRR genes was not predictive of PFS benefit with the addition of olaparib to bevacizumab as first-line maintenance. Of interest, in the small non-BRCA population with HRR mutations, HRD by genomic instability testing was still predictive of benefit from olaparib.

Adding PARP Inhibitors to Bevacizumab in Stage III Ovarian Cancer
Bevacizumab has been approved for several years in combination and as maintenance of frontline chemotherapy for advanced ovarian cancer. With the advent of PARP inhibitors, the question became whether combining these agents is beneficial. According to the National Comprehensive Cancer Network, patients with ovarian cancer who received bevacizumab as part of primary therapy should be assessed for BRCA1/2 mutations. Those with wild-type or unknown BRCA1/2 status and a response can receive bevacizumab maintenance if HRP or bevacizumab plus olaparib if HRD is present. Those with germline or somatic BRCA1/2 mutations and a response should preferentially receive the combination of bevacizumab plus olaparib but also can receive olaparib or niraparib as monotherapy.

One question has been whether patients with stage III ovarian cancer and a BRCA1/2 mutation benefit from the addition of a PARP inhibitor to bevacizumab. Indirect data have been provided by studies such as the randomized phase II AVANOVA2 trial, which examined the impact of adding bevacizumab to niraparib in patients with platinum-sensitive recurrent ovarian cancer. In AVANOVA2, a substantial improvement in investigator-assessed PFS was observed with the addition of bevacizumab to niraparib (12.5 vs 5.5 months, respectively). In a subgroup analysis based on BRCA status, the PFS benefit was more prominent in the wild-type BRCA patient cohort vs those with tumors harboring mutated BRCA. However, there was no significant overall survival benefit to niraparib plus bevacizumab vs niraparib alone.

Vergote and colleagues conducted a population-adjusted indirect comparison of the SOLO1 and PAOLA-1 studies (SOLO1: N = 380; PAOLA-1: N = 222), which enrolled patients with stage III/IV ovarian cancer undergoing frontline chemotherapy. In this analysis, which used a propensity score method to adjust for discrepancy in patient characteristics, adding olaparib to bevacizumab seems to improve PFS vs olaparib alone in patients with newly diagnosed, BRCA-mutated disease. Approximately 80% of patients had stage III ovarian cancer. With the caveat that this is a nonrandomized comparison, results showed a median PFS of 82% for the combination vs 73% for olaparib alone vs 50% for bevacizumab plus placebo vs 36% for placebo.

Your Thoughts?
What are your questions and thoughts on the current management of ovarian cancer using PARP inhibitors? I encourage you to answer the polling question and share your thoughts in the discussion box below.

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