BRCA1/2 mutations lead to a high risk of developing breast cancer and ovarian cancer and are also associated with other tumor types including prostate, colon, stomach, pancreas and gall bladder. In particular, BRCA1- and BRCA2-mutated breast cancers (accounting for about 5% of all breast cancer cases in the United States), predispose affected patients to more aggressive disease. In 2018, the FDA approved both AstraZeneca/Merck’s Lynparza (olaparib) and Pfizer’s Talzenna (talazoparib), two PARP inhibitors, for the treatment of BRCA-mutated breast cancers. PARP inhibitors are targeted cancer therapies that inhibit the Poly (ADP-ribose) Polymerase, or PARP, an enzyme involved in DNA repair through homologous recombination (HR) and genomic stability. Through a process known as synthetic lethality, which inhibits the HR process in BRCA1- or BRCA2-defective cells, these drugs induce the cancerous cells to die. In recent years, two other PARP inhibitors (niraparib and rucaparib) have been approved for patients with inherited BRCA mutations.
Many breast cancers today are caught early, thanks to widespread screening. In some patients with aggressive cancers at high risk of recurrence, adjuvant treatments such as chemotherapy, radiation therapy, or adjuvant immunotherapy are used to increase chances of achieving a cure. At ASCO this year, new data was presented on Lynparza’s use as adjuvant therapy in early stage HER-2 negative breast cancer patients with BRCA1 or BRCA2 mutations who were at high risk of disease recurrence.
Results from the Phase 3 OlympiA trial of Lynparza showed that when the PARP inhibitor was given post-surgery to such patients, it reduced the risk of distant tumor recurrence or death by 43%, including in those with triple negative and hormone-receptor-positive breast cancers. At three years post-treatment, 85.9% of the Lynparza-treated patients were still alive and free of invasive breast cancer versus 77.1% of placebo-treated patients. While the data on overall survival of trial participants is not yet mature at the 2.5 years median follow up, the survival curve for the Lynparza-treated population has been trending positively, with a 32% reduction in overall risk of death reported to date. The study remains ongoing to read out overall survival.
Shortly following the presentation and publication of this compelling data, ASCO changed its breast cancer management guidance to recommend a year of adjuvant therapy with Lynparza for all patients with high-risk, early-stage, HER2-negative breast cancer harboring germline BRCA1 or BRCA2 mutations. This makes Lynparza the first PARP inhibitor likely to change the standard of care for such early-stage breast cancer patients.
While PARP inhibitors are clearly becoming game changers for some patients with BRCA-mutated breast tumors, their long-term use may be less clear in other settings because patients invariably develop resistance to these treatments over time.
In June, two separate research teams announced the discovery of a new enzyme target, POLQ, that is essential for the survival of BRCA1- and BRCA2-mutated cells and may provide new treatment options for patients who have developed PARP inhibitor resistance. Like PARP inhibitors, POLQ inhibitors also leverage the synthetic lethality principle. The U.K.-based Institute of Cancer Research and Artios Pharma published research in Nature Communications showing the ability of small-molecule POLQ inhibitors to block DNA repair in BRCA-mutated cancer cells without affecting normal cells. Moreover, in rat models, the POLQ inhibitors were observed to shrink BRCA-mutated tumors that had become resistant to PARP inhibitors. Artios now plans to initiate a clinical trial with its POLQ inhibitor by the end of 2021, both as a single agent and in combination with PARP inhibitors or other DNA-damaging agents.
U.S. researchers at Dana Farber Institute also published research in June, in Nature Cancer, showing that a 50-year-old antibiotic, novobiocin, could target POLQ to kill BRCA-mutated tumor cells and reduce the size of tumors in animal models, including PARP inhibitor-resistant ones. The team is now planning a clinical trial with novobiocin in patients with BRCA-mutated cancers resistant to PARP inhibitors.