PARP Inhibitor Maintenance SCORES in Ovarian Cancer
Abstract & Commentary
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, HoustonI, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman reports no financial relationships relevant to this field of study.
Synopsis: Olaparib, a PARP inhibitor, significantly improved progression-free survival among platinum-sensitive recurrent high-grade ovarian cancer patients when administered as a maintenance agent. Patients were not preselected for BRCA1 or BRCA2 mutation carrier status, highlighting the role for this class of agent in tumors with homologous recombination deficiency.
Source: Ledermann J, et al. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med 2012;366:1382-1392.
Poly(adenosine diphosphate [adp]-ribose) polymerase (PARP) is an enzyme participating in low-fidelity DNA repair of single strand breaks. Pharmacologic inhibition of PARP has shown to be effective in tumors lacking homologous recombination, such as those harboring silencing mutations of BRCA1 and 2. However, clinical activity also has been demonstrated in patients without these mutations. These observations led to a randomized, double-blind, Phase 2 trial of maintenance olaparib, an oral PARP inhibitor, vs placebo in women with platinum-sensitive, high-grade serous ovarian cancer who had achieved at least a partial response to their antecedent platinum-based chemotherapy. Patients were not required to have germline mutation in BRCA1 or 2. The primary endpoint was progression-free survival (PFS). Olaparib (400 mg BID orally) was administered until disease progression or unacceptable toxicity. Three hundred twenty-six patients were registered and 265 met eligibility criteria. PFS was significantly longer with olaparib than with placebo (median, 8.4 months vs 4.8 months; hazard ratio [HR] 0.35; 95% confidence interval 0.25 to 0.49; P < 0.001). The effect was consistent across all subgroups, including BRCA status, of which approximately 22% in both groups carried germline BRCA1 or 2 mutation and approximately 14% in both groups were known wild type; the remainder were unknown. The median number of prior platinum regimens and prior chemotherapy regimens were 2 and 3, respectively, although some patients had substantially more prior therapy. Adverse events more commonly reported in the olaparib arm were nausea (68% vs 35%), fatigue (49% vs 38%), vomiting (32% vs 14%), and anemia (17% vs 5%); however, the majority of adverse events were grade 1 or 2. Although the data are immature (just 38% of events recorded), no benefit was seen on overall survival. The study confirmed activity of olaparib in high-grade, serous, relapsed, platinum-sensitive ovarian cancer. No new safety signals were detected in this largest cohort of treated patients.
Commentary
"Individualized therapy" is an easy concept to comprehend, but an extremely difficult one to enact for patients with ovarian cancer. While making informed decisions about specific therapy through some interrogation of a patient's tumor should translate to better outcomes, our ability to find the biological "Achilles heel" at any one time — or even more challenging, over time — is tragically limited. This is due in part to insensitivity of our methods to identify key vulnerabilities, the limitation of known targets, the inability to hit targets-of-interest pharmacologically, the lack of reproducible methods to assess tumor biology in a serial manner or in response to treatment, the spatial heterogeneity of the oncogenic process (primary vs metastases, tumor vs stroma, central tumor vs periphery, etc.), and the genomic instability of ovarian cancer in general.1 However, despite these limitations, patients with tumors deficient in homologous recombination processes (HRD) are a genetic "set-up" for therapy exploiting other compensatory DNA repair mechanisms for survival, such as PARP. Either event (HRD or inhibition of PARP) is not universally lethal; however, PARP inhibition in the setting of HRD is lethal — a strategy also known as "synthetic lethality."2
It has been previously well described that the BRCA genes are important regulators of high-fidelity homologous recombination repair of double-stranded DNA injury. Their functional absence is easiest to see in patients who carry a germline mutation; however, data from the Cancer Genome Atlas (TCGA) have demonstrated that tumors can develop BRCA malfunction either by somatic mutation or via epigenetic silencing through promoter methylation.3 In addition, several other genes that contribute to homologous recombination repair processes are frequently altered in high-grade serous ovarian cancer, bringing the potential audience for this individualized therapy (PARP inhibitors) to near 50%.
The current study tested this hypothesis by using clinicopathologic features of HRD: high-grade serous ovarian cancer and platinum sensitivity. While these are crude methods to identify a potential population likely to individually gain from the impact of PARP inhibition, the effect from treatment was dramatic! The HR for PFS is among the lowest ever recorded in an ovarian cancer clinical trial with any therapy. In this study, olaparib was used as an agent to maintain the best treatment effect from a prior platinum therapy; about half of the study population had disease when they were randomized, which explains the shorter than expected duration of progression in the placebo group. Nevertheless, a clear benefit was documented and in the confines of no new safety signals. What would further the "individualized" moniker for this therapeutic strategy would be a test to identify those high-grade serous tumors where HRD was present at the time of treatment. Such strategies, like a RAD51 assay, are currently being pursued.4,5
The issue as to whether this class of agent has a role in ovarian cancer management and meets the broadest definition of "individualized therapy" is not largely debated; determining a path to regulatory approval is. The focus on treatment programs that improve only overall survival (immature, but not suggested in this study) has severely hampered clinical development, including this specific agent, which, until just recently was tabled for further development. Fortunately, the current trial's results have sparked renewed interest among companies and investigators and new protocols, including chemotherapy combinations and other biological agents (e.g., anti-angiogenesis and PI3K inhibitors), are planned or in motion offering new hope for effective therapy for these patients.6
References
- Gerlinger M, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-892.
- Farmer H, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-921.
- Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-615.
- Lu W, et al. Mutation screening of RAD51C in high-risk breast and ovarian cancer families. Fam Cancer 2012; Apr 4 [Epub ahead of print].
- Mukhopadhyay A, et al. Development of a functional assay for homologous recombination status in primary cultures of epithelial ovarian tumor and correlation with sensitivity to poly(ADP-ribose) polymerase inhibitors. Clin Cancer Res 2010;16:2344-2351.
- Dedes KJ, et al. PTEN deficiency in endometrioid endometrial adenocarcinomas predicts sensitivity to PARP inhibitors. Sci Trans Med 2010;2:53ra75.
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