PARP, a protein, helps repair DNA when it becomes damaged. PARP inhibitors are a type of targeted therapy; in cancer treatment, blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are approved as therapeutic and maintenance therapy across a small selection of cancer types, often for patients with BRCA mutations.
AstraZeneca has already seen stellar success with its PARP treatment, Lynparza (olaparib), the first PARP inhibitor approved in 2014 for treating germline BRCA-mutated metastatic ovarian cancer after three or more lines of chemotherapy. The company reported significant sales growth in 2020 for olaparib in February.
However, AZD5305 is reportedly designed to improve on that drug’s capabilities, in other words, it could work just as efficiently as olaparib but without the known side effects.
Jeffrey Johannes, PhD, from AstraZeneca’s oncology team, discussed the background to the development of AZD5305 during a talk at AACR 2021.
The hypothesis for its development was that a selective PARP1 inhibitor and DNA trapper may improve the therapeutic index versus first-generation PARP inhibitors.
“When looking across the landscape of existing PARP inhibitors, we saw an opportunity in exploring the potential differentiation of a PARP1 inhibitor that is selective against PARP2 and other PARP family members, and clean with respect to secondary pharmacology [effects of a substance not related to its desired therapeutic target],” Johannes said.
A growing body of evidence suggests that PARP2 is linked to hematological toxicity, a decrease in bone marrow and blood cells, which may lead to infection, bleeding, or anemia, and one of the main clinical adverse events observed with first generation PARP inhibitors.
Combining PARP treatment with other agents
The preclinical data around AZD5305 shows how it could potentially allow patients to stay on treatment longer, said Susan Galbraith, senior vice president and head of research and early development, oncology R&D at AstraZeneca, in a release.
“This innovative molecule is designed to optimize the therapeutic window of PARP inhibition, providing new opportunities for combination treatment with chemotherapy and targeted medicine,” she added.
There has been an increasing focus on clinical strategies that combine PARP inhibitors with other agents; PARP inhibitors are said to act as sensitizers for chemotherapies, immunotherapies, and targeted agents.
A Phase 1 clinical study on AZD5305 got underway in November last year; it is evaluating whether experimental treatment with the next generation treatment alone, or in combination with anti-cancer agents is safe, tolerable, and has anti-cancer activity in patients with advanced solid tumors.