Breast cancer (BC) is the second most common cancer in the world and the most common malignancy in women, with men accounting for fewer than 1% of patients that suffer it. Although survival rates are improving, BC is still the fourth most common cause of death from cancer worldwide. [1]
Most cases of BC are caused by acquired (somatic) DNA mutations, however up to 10% of patients with BC have inherited (germinal) DNA mutations, which often lead to loss of function in genes involved in DNA repair. BRCA1 and BRCA2 are examples of such genes.
A family of drugs called PARP inhibitors have been proved to be particularly good at killing cancer cells with mutations in the genes BRCA1 or BRCA2. In 2014, the European Medicines Agency (EMA) approved the PARP inhibitor olaparib for women with ovarian cancer who have an inherited BRCA1 or BRCA2 mutation, becoming the first cancer drug to be approved that is directed against an inherited genetic mutation. Later on, the EMA approved the use of olaparib for women with advanced BC and an inherited BRCA mutation. Recently, in 2020, the United States’ Food and Drug Administration (FDA) also approved olaparib for the treatment of metastatic castration-resistant prostate cancer with mutations in homologous recombination repair (HRR) genes. Other PARP inhibitors such as talazoparib, niraparib and rucaparib have also been approved for treatment of advanced BC, advanced ovarian cancer and advanced prostate cancer, respectively, and ongoing studies are investigating the use of PARP inhibition in other cancers too, including brain cancer.
Last week, promising results of the OlympiA trial were presented at the American Society of Clinical Oncology (ASCO) meeting. The OlympiA trial was a phase III, double-blind, randomized trial involving patients with human epidermal growth factor receptor 2 (HER2)–negative early BC with BRCA1 or BRCA2 germline variants. Patients were randomly assigned to receive either olaparib or placebo for one year as adjuvant treatment.
The results, which have been published in the New England Journal of Medicine, show that giving olaparib to patients that have had their tumors surgically removed and that have completed a regimen with chemotherapy cuts the risk of breast cancer returning or spreading in women who have inherited mutations in their BRCA1 or BRCA2 genes. Adjuvant treatment with olaparib was associated with significantly longer survival free of invasive or distant disease than placebo: 3-year invasive disease-free survival was 85.9% in the olaparib group and 77.1% in the placebo group (hazard ratio 0.58; P<0.001), while 3-year distant disease-free survival was 87.5% in the olaparib group and 80.4% in the placebo group (hazard ratio 0.57; P<0.001).
Although PARP inhibitors are mainly used to treat metastatic tumors, these results prove that they can also be effective in the treatment of early BC, and raise the possibility that PARP inhibitors could be effective as adjuvant treatment in other BRCA1- and BRCA2-altered cancers. Further trials are in development to explore this possibility.
At MEDSIR we are also investigating the use of PARP inhibition as treatment for different subtypes of BC patients, but not only for those with BRCA1 and BRCA2 germinal mutations, but also for patients with other alterations that cause a deficiency in the homologous recombination DNA repair mechanism. Exploiting those alternative vulnerabilities in a targeted way may open doors to selecting additional subgroups of patients that might benefit from personalized treatments with PARP inhibitors. Ongoing clinical trials sponsored by MEDSIR that use PARP inhibitors include the NOBROLA study (in triple-negative BC patients), the OPHELIA study (in HER2-positive BC patients) and the LUZERN study (in luminal BC patients).
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[1] Sung et al, Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. Ca Cancer J Clin, 2021
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