PARP inhibitors: Beyond hereditary ovarian cancer?
Poly(ADP-ribose)polymerase (PARP) inhibitors are showing considerable promise for the treatment of BRCA mutation-associated ovarian and breast cancer. This approach exploits a synthetic lethal strategy to target the specific DNA repair pathway in cancers that harbour mutations in the BRCA1 or BRCA2 genes.
Accumulating evidence suggests that the promising activity of PARP inhibitors may not be limited to tumours with BRCA mutations but that PARP inhibitors may also show activity in tumours having the property of “BRCAness”. This describes the situation whereby a homologous recombination (HR) DNA repair defect is present but no germline BRCA 1 or BRCA2 mutation is detected. In June 2011, the Cancer Genome Atlas Research Network published the results of integrated genomic analyses of high-grade, serous ovarian cancer (Nature. 2011 Jun 29;474(7353):609-15). In this study, defective homologous recombination was present in approximately 50% of all high-grade serous ovarian cancer cases. This provides a strong biological rationale for clinical trials of PARP inhibitors targeting cancers with homologous recombination deficiency.
At ASCO June 2011, exciting results of PARP inhibitors as maintenance therapy in sporadic ovarian cancer were presented by Prof Johnathan Ledermann, professor of medical oncology at UCL Cancer Institute, University College London, UK.
This was a randomised placebo-controlled phase II study in which single agent olaparib was administered as a maintenance treatment to patients with high-grade serous ovarian cancer (including non-BRCA mutant ovarian cancer) after completion of chemotherapy for platinum-sensitive relapsed disease (2 or more previous platinum regimens). 265 women who had maintained partial or complete response after their last platinum-containing regimen were randomised to oral olaparib 400 mg bd (n=136) or placebo (n=129). The primary end point of the study was progression-free survival by RECIST; secondary end points included time to progression by CA-125 (GCIG criteria) or RECIST, overall survival, and safety.
The primary endpoint was achieved: PFS by RECIST was significantly longer in the olaparib group compared to the placebo group (HR, 0.35; 95% CI 0.25–0.49; P<0.00001; median 8.4 vs 4.8 months). The time to progression by CA-125 or RECIST was also significantly prolonged in the olaparib arm compared with placebo (HR, 0.35; 95% confidence interval, 0.25 to 0.47; P<0.00001, median 8.3 vs 3.7 months). A lower risk of disease progression was seen across all subgroups analysed. At the time of data analysis, the data were too immature for analysis of overall survival benefit.
Common adverse events (all grades) included nausea (68% vs 35%), fatigue (49% vs 37%), vomiting (31% vs 14%), and anaemia (17% vs 5%). The majority of events were grade 1 or 2. The most common grade 3 or 4 toxicities were fatigue (7% vs 3%) and anaemia (5% vs 1%).
This is the first randomised trial to demonstrate the benefits of a PARP inhibitor as maintenance therapy in platinum-sensitive, relapsed, high-grade serous ovarian cancer and provides clear evidence for a role of PARP inhibitors in non-BRCA mutant ovarian cancer. The overall survival results are eagerly awaited. These findings provide strong support for further clinical trials to address the role of PARP inhibitors in the management of sporadic ovarian cancer.
A major challenge is the identification of patients that are most likely to benefit from treatment. Patients with HR-deficient cancers appear to be more likely to derive benefit. The question is how can they be identified for treatment? One option is to measure the formation of nuclear RAD51 foci after DNA damage. Gene expression or immunohistochemical signatures of deficiency of BRCA1 or BRCA2 expression or HR defects and functional assays are also being explored.
J. A. Ledermann, P. Harter, C. Gourley, M. Friedlander, I. B. Vergote, G. J. S. Rustin, C. Scott, W. Meier, R. Shapira-Frommer, T. Safra et al: Phase II randomized placebo-controlled study of olaparib (AZD2281) in patients with platinum-sensitive relapsed serous ovarian cancer (PSR SOC). J Clin Oncol 2011, 29 (suppl; abstr 5003).