Mechanism of Cediranib–Olaparib Combo Revealed

The combination of olaparib (Lynparza; AstraZeneca) and cediranib (Recentin; AstraZeneca) has shown promise in recurrent non–BRCA-mutant ovarian cancer, and a recent study offers a possible mechanistic explanation: Cediranib may confer sensitivity to olaparib by increasing tumor hypoxia and inhibiting platelet-derived growth factor receptor (PDGFR), which reduces BRCA1/2 and RAD51 expression, thus decreasing homology-directed DNA repair (Sci Transl Med 2019;11:eaav4508).

A PARP inhibitor, olaparib was developed for patients with cancers such as ovarian and breast that harbor BRCA mutations, which interfere with DNA repair, thus making cancer cells more dependent on PARP to fix DNA. However, in a 2014 phase II trial, combining olaparib with the antiangiogenic VEGFR inhibitor cediranib significantly increased progression-free survival in patients with recurrent, platinum-sensitive non–BRCA-mutant ovarian cancer compared with olaparib alone (16.5 months vs. 5.7 months; Lancet Oncol 2014;15:1207–14).

“That was something that was a little bit unexpected but was initially explained by the idea that the inhibition of angiogenesis would lead to decreased oxygen delivery—and therefore, a state of hypoxia in the tumors,” says Peter Glazer, MD, PhD, of Yale University in New Haven, CT, senior author of the new study. “We were interested to see if hypoxia-induced DNA-repair deficiency would explain the results.”

Glazer and his team set out to test this hypothesis and characterize other potential mechanisms underlying the apparent synergistic interaction between olaparib and cediranib. In a series of experiments using patient-derived mouse xenografts of ovarian and breast cancers, the researchers found that cediranib did induce hypoxia, which decreased BRCA1/2 and RAD51 expression, causing a DNA-repair deficit that made cancer cells sensitive to olaparib. However, they noticed that even nonhypoxic cells had decreased DNA repair, a result they confirmed using ovarian cancer cells in culture.

The researchers then conducted follow-up experiments on patient-derived cancer cell lines in culture, establishing that cediranib decreases DNA repair by acting on the PDGFR pathway: The drug inhibits PDGFR signaling, which activates protein phosphatase 2A and, subsequently, the E2F4/p130 transcriptional corepressor, downregulating expression of BRCA1/2 and RAD51.

“We think it's a dual effect, and in fact there may be other effects of cediranib, because one of the things we learned is cediranib is quite potent for the VEGF receptor for which it was developed, but it also inhibits other receptor tyrosine kinases, including the PDGF receptor,” Glazer says. “I think it highlights that this is a potentially viable approach to developing DNA-repair inhibitors that is distinct from directly drugging the repair enzymes.”

Currently, studies are investigating olaparib plus cediranib in an array of solid tumors that lack BRCA mutations, such as prostate and pancreatic cancers. Glazer is also interested in whether PDGFR expression could be used to predict patient responses.

“It's gratifying to see continued understanding of why we're seeing a synergistic effect of putting a PARP inhibitor together with a drug that has antiangiogenic properties—it provides preclinical rationale for why you would test the combination,” says Ursula Matulonis, MD, of Dana-Farber/Harvard Cancer Center in Boston, MA, who led the phase II trial, but was not involved in the new study.

Matulonis wants to know how these preclinical results will translate into the ongoing phase III GY004 and GY005 trials testing the combination in patients with recurrent ovarian cancer. “The question is going to be in the case of this drug combination, ‘Is what happens in the mouse model really what happens in a human patient?’” –Catherine Caruso

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