On March 27, the FDA gave Tesaro a broad approval for its PARP inhibitor, niraparib, as maintenance therapy for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after a complete or partial response to platinum-based chemotherapy. The FDA decision came well in advance of the PDUFA date set for June 30, and approves the drug for very broad usage — not just for patients irrespective of their BRCA mutation status but also for use in both HRD positive and HRD negative patients.
Tesaro will market the drug under the brand name ZEJULA. Tesaro’s Phase 3 data for niraparib, presented in Fall 2016, showed a 73% reduction in the risk of tumor progression compared to placebo, and a 21-month delay in tumor progression compared to 5.5 months for placebo in patients who had a germline BRCA mutation. In patients without such a BRCA mutation, median progression-free survival was 9.3 months compared to 3.9 months for similar patients on placebo.
PARP inhibitor development has become a very competitive area for oncology drug development. In mid-March, AstraZeneca released top-line data from a Phase 3 study of once-daily tablet-form LYNPARZA (olaparib) as maintenance therapy in women with ovarian cancer with germline-mutated BRCA mutations whose tumors had previously responded to platinum-based chemotherapy. The results showed a progression-free-survival of 30.2 months for the LYNPARZA-treated women versus 5.5 months for those receiving a placebo. Approximately 11% of the study participants discontinued the trial due to side-effects, the most serious of which were anemia, neutropenia and mild thrombocytopenia. But the oncology community — as well as the stock market — was excited by the bottom-line message that LYNPARZA could reduce the risk of ovarian tumor progression by 75%. LYNPARZA is already approved in the United States for ovarian patients no longer responsive to three or more prior therapies, and in Europe, as second line maintenance therapy.
PARP inhibitors like ZEJULA and LYNPARZA work by blocking the enzyme poly (ADP-ribose) polymerase that mediates DNA damage repair in tumor cells after chemotherapy. While BRCA mutations are associated with harder-to-treat breast and ovarian cancers, they also inhibit DNA repair, enabling PARP inhibitors to work better in patients whose tumors exhibit such mutations.
Clovis also recently received FDA approval for its PARP inhibitor, Rubraca (rucaparib), for the treatment of BRCA-mutant ovarian tumors no longer responsive to two or more therapies. Pfizer and Abbvie also have PARP inhibitors in clinical trials. Beyond ovarian cancer, such drugs are also being tested against breast, prostate and lung tumors.
Ultimately, many analysts believe the drugs will prove to be relatively interchangeable in terms of their anticancer effects. Moreover, AstraZeneca itself is talking about the benefits of LYNPARZA as maintenance therapy in terms of a “reduced pill burden and safety consistent with previous trials.” Hence the safety and tolerability of olaparib versus niraparib may ultimately be its differentiating factor.
In addition, companies may look to biomarker strategies as a potential means of differentiation. Already, companies are taking different approaches as AstraZeneca and Clovis have pursued a BRCA mutant indication while Tesaro’s niraparib has a broad indication regardless of BRCA or HRD status. HRD status, which is measured using a panel of markers (including BRCA) for DNA repair, has been thought of as a potential way to broaden the indication beyond BRCA. Beyond BRCA and HRD, Clovis’ deal with Foundation Medicine was designed to identify biomarkers beyond germline BRCA in the form of a BRCAness signature. The PARP inhibitor field is shaping up to be complex when it comes to biomarkers, and raises the question of whether a novel biomarker strategy will provide players with compelling differentiation in the market.