AstraZeneca’s poly(ADP-ribose) polymerase (PARP) inhibitor, Lynparza (olaparib), had enjoyed two years alone on the ovarian cancer market without direct competition until Clovis Oncology’s Rubraca (rucaparib) joined the party two months ago.
In the US, Lynparza is indicated for the fourth-line treatment of patients with a breast cancer susceptibility gene (BRCA) mutation, and Rubraca received a label for the third line in the same patient population. Although this was a win for Clovis, AstraZeneca is set to punch back after it announced top-line results from its Phase III SOLO-2 study, which investigated Lynparza use in the second-line treatment setting. The full results from this study are set to be presented on Tuesday, March 14, 2017 at the Society of Gynecologic Oncology Annual Meeting during the late-breaking abstract scientific plenary VI. AstraZeneca is expected to receive full approval and a label expansion in 2017 based on the data from the SOLO-2 trial.
Cells with inactive BRCA proteins caused by inherited or acquired mutation have difficulty repairing double-stranded DNA (dsDNA) breaks by homologous recombination and rely on other repair proteins, like PARP, to detect these breaks and fix them. Therefore, the inhibition of PARP in cancer cells that harbor BRCA-inactivating mutations restricts the cell’s ability to repair DNA and induces death by synthetic lethality. Other mutations, beyond BRCA, impair a cell’s ability to repair dsDNA breaks and would be targets for PARP inhibition. This patient population has been coined “BRCA-like” and increases the group of ovarian tumors that would be eligible for drug treatment.
Tesaro’s niraparib is looking to gain approval in not only BRCA-mutated and BRCA-like patients, but in all platinum-sensitive recurrent patients based on strong progression-free survival data obtained from its Phase III NOVA trial. The drug is set to hit the market by the first half of this year. Tesaro will be armed with a larger label patient population than Lynparza and solid data to start to win over physicians who have prescribed Lynparza over the last two years.
While a plethora of PARP inhibitor drug choices may exist in the coming years, many unanswered questions still remain. Drug companies may be able to differentiate themselves from the crowded field if they can provide answers. Questions such as: When in the treatment pathway should PARP inhibitors be used? Are they best used as maintenance treatment after chemotherapy, as monotherapy for active treatment, or in combination with chemotherapy? What are the molecular mechanisms responsible for resistance, and can they be overcome? Can patients be re-treated with the same or a different PARP inhibitor later in the treatment paradigm? Answers to these questions in combination with robust efficacy and safety data would be a strong 1-2 punch to help knock out the competition and achieve commercial success.