Unlike in most other cancers, where targeted therapies are significantly changing the treatment paradigm, precision medicine is yet to arrive in the clinic for the treatment of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer. The heterogeneous nature of the disease and lack of information on genetic drivers are major factors contributing to the slow clinical development of targeted therapies in PDAC. Some of the most common somatic mutations in PDAC are KRAS (>90%), CDKN2A (>95%), TP53 (>75%), and SMAD4 (>55%). While focusing on these alterations for drug development is a sensible strategy due to their high incidence in PDAC, it has been extremely difficult to directly target them and all attempts in the clinic have so far failed.     

A promising emerging target in PDAC is BRCA1 and BRCA2 (BRCA1/2), which are mutated in 5-8% of the overall pancreatic cancer population and are associated with hereditary pancreatic cancer. BRCA1/2 encode for proteins that maintain genomic stability via the repair of DNA double-strand breaks (DSBs). In patients with BRCA1/2-mutated tumours, tumour cells are viable and can use alternative repair pathways to prevent DNA damage caused by the loss of the DNA DSB repair pathway. However, the lack of functional BRCA1/2 renders these tumors particularly sensitive to DNA-damaging agents such as platinum. Therefore, an effective antitumor strategy in this context is to trigger simultaneous loss of an alternative DNA repair pathway, as this would cause excessive DNA damage and result in the death of BRCA1/2-mutated tumor cells. This rationale was tested by inhibiting the poly-ADP ribose polymerase (PARP) family of proteins, which regulate repair of DNA single-strand breaks (SSBs), and proved to be highly effective in BRCA1/2-mutated ovarian cancer.

Multiple PARP inhibitors (PARPi) have been approved for the treatment of ovarian cancer and are currently in clinical development for PDAC. AstraZeneca’s Lynparza (olaparib) is the frontrunner in the pancreatic cancer space and is positioned in the maintenance setting for the treatment of germline BRCA1/2-mutated metastatic PDAC that has responded to first-line treatment. The contenders Clovis Oncology and AbbVie are undertaking diverse approaches to catch up with AstraZeneca and distinguish their respective PARPis, Rubraca (rucaparib) and veliparib. Rubraca is directly competing with Lynparza due to its positioning in the same treatment setting. However, Rubraca is targeting a wider patient population that includes patients with germline and somatic BRCA1/2 mutations as well as other DNA repair-associated mutations such as those in PALB2, which would correspond to approximately 10-12% of the overall pancreatic cancer population. AbbVie is investigating veliparib in combination with gemcitabine + cisplatin in the much larger treatment-naïve metastatic PDAC population. To further increase its prospective market share in PDAC, veliparib is also being evaluated in combination with other chemotherapy regimens in later treatment lines in metastatic PDAC.

"When other alterations with BRCA-like phenotype are taken into account, the eligible target population for PARPis could expand considerably to approximately 25% of the overall pancreatic cancer population."

Although there is not as much clinical data for PARPis in PDAC as in ovarian cancer, small sample-size studies have shed some light on the most clinically viable positioning of PARPis in metastatic PDAC. AstraZeneca initially tested Lynparza in combination with irinotecan, cisplatin, and mitomycin C in newly diagnosed metastatic PDAC. Lynparza resulted in substantial toxicity in this combination, preventing further development of the regimen. Based on this finding, it may not be a feasible strategy to use PARPis in combination with chemotherapy. To this end, AbbVie may have taken a high-risk approach, as the majority of veliparib’s clinical development in PDAC consists of combination regimens. Similarly, Clovis turned its attention to the maintenance setting following initial evaluation of Rubraca in later treatment lines. In heavily treated patients with locally advanced/metastatic BRCA1/2-mutated PDAC, the lack of response to treatment with Rubraca in the first evaluable patient cohort prompted Clovis to stop further enrollment. An interesting finding of this trial indicated that Rubraca was more effective in less heavily pretreated patients; the only patients who responded to Rubraca had received one prior line of therapy, suggesting a potential use for Rubraca in earlier treatment lines in metastatic PDAC.

Despite the initial setbacks in their clinical development, there is considerable growth opportunity for PARPis in PDAC. Although initially positioned specifically for patients with BRCA1/2- and PALB2-mutated metastatic PDAC, the available clinical data in ovarian cancer indicated a clinical benefit for PARPis beyond this subpopulation. When other alterations with BRCA-like phenotype are taken into account, the eligible target population for PARPis could expand considerably to approximately 25% of the overall pancreatic cancer population. While this would be a sizeable patient population, there may be further label expansion opportunity for PARPis in PDAC.

If clinical efficacy is confirmed, such a scenario could result in further expansion of the eligible target population beyond BRCA-like metastatic PDAC for practical reasons. In line with recent label expansions in ovarian cancer, the FDA may undertake a similar approach in earlier treatment lines in metastatic PDAC and approve PARPis regardless of mutation status, as it would be time-consuming and costly for a patient to undergo screening for multiple mutations in order to be identified with a BRCA-like phenotype. Whether or not the FDA grants a wider label approval for PARPis, the highly underserved pancreatic cancer population will soon have multiple effective targeted treatment options for patients with tumors exhibiting BRCA-like features. 

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GlobalData (2017). OpportunityAnalyzer: Pancreatic Cancer – Opportunity Analysis and Forecasts to 2026, to be published