Analyst Notes: The PARP inhibitors represent a breakthrough in the treatment of ovarian cancer and AstraZeneca is firmly placed in the driving seat

Preclinical evidence began to emerge in the 1990s to suggest that the inhibition of poly (ADP-ribose) polymerase (PARP) reduced survival in BRCA1 and BRCA2 deficient cells. PARP inhibitors have since become the focus of intense interest within pharma, particularly in the context of the potential to treat BRCA–mutation positive ovarian and breast cancer.

AstraZeneca's Lynparza (olaparib) became the first PARP inhibitor to gain approval for ovarian cancer when it secured landmark FDA and European Medicines Agency approvals in December 2014 for maintenance therapy in relapsed BRCA-mutated tumours. Importantly, this also represented the first product approval for ovarian cancer to be based on the pre-selection of patients. Clovis Oncology's rucaparib and Merck & Co./Tesaro's niraparib are also in Phase III development for the treatment of ovarian cancer.

Insights, Analysis & Views

Leading key opinion leaders (KOLs) consulted for a new report published by FirstWord, entitled Ovarian Cancer: KOL Insight, A new era of targeted therapy, are optimistic regarding the addition of PARP inhibitors to the treatment algorithm for ovarian cancer. Indeed, it's highlighted as a major breakthrough.

"As a class of drug, the PARP inhibitors have been one of the most exciting new breakthroughs in the last decade. People talk about the PARPs in the same way as the introduction of platinum in the 1970s, and the introduction of Taxol in the 1990s. Now in the early 2010s, here is a new class of drugs that are clearly active and pretty well tolerated, certainly when given as single agents." - EU Key Opinion Leader

The data from the Phase II Study 19 of Lynparza has provided significant fuel for this optimism. This trial evaluated Lynparza as first-line maintenance therapy for platinum-sensitive relapsed BRCA-mutated high-grade serous epithelial ovarian cancer. Study 19 data indicated that Lynparza treatment was associated with a median progression-free survival (PFS) of 11.2 months, compared with 4.3 months for the placebo arm (hazard ratio: 0.18; p<0.0001), in patients with a BRCA mutation (germline and/or somatic).

KOLs are impressed by the magnitude of the PFS benefit reported from Study 19 and predict that Lynparza will become widely used as maintenance therapy in BRCA-mutation positive ovarian cancer. However, efficacy needs to be substantiated in Phase III trials to secure Lynparza's positioning.

Interestingly, as KOLs point out, there remain a number of unanswered questions relating to Lynparza. Firstly, there may be wider opportunities for Lynparza beyond BRCA-mutation negative disease. In particular, it's proffered that those BRCA-mutation negative patients who share common phenotypic traits with BRCA germline mutation carriers (termed 'BRCAness') might be a subgroup likely to benefit. Additional, and as yet unidentified, molecular abnormalities underlie these characteristic traits and may also be able to drive future treatment decisions.

Furthermore, a recent publication in Nature presents evidence suggesting that ovarian tumours expressing abnormally high levels of the polymerase Q enzyme (POLQ) benefit from treatment with Lynparza. Hence these findings may lead to the identification of another group of patients who are suitable candidates for this treatment.

In the new Ovarian Cancer: KOL Insight FirstWord report, KOLs also discuss the potential of Lynparza to be used in maintenance therapy in earlier therapy lines; however, its administration to patients earlier in their disease course raises concern among the specialists with regard to its longer-term safety. As the evidence base for use of the PARP inhibitors in ovarian cancer becomes more established, KOLs hope that the true potential of these agents will be realised.

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