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Benefit of AstraZeneca's Cediranib Plus Lynparza May Be Limited to HRR-Deficient Prostate Cancers

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NEW YORK – In metastatic castration-resistant prostate cancer (mCRPC), the progression-free survival benefit of adding AstraZeneca's investigational VEGF inhibitor cediranib to the PARP inhibitor olaparib (AstraZeneca/Merck's Lynparza) may be limited to patients with homologous recombination repair (HRR)-deficient cancers, according to a new biomarker analysis presented Thursday during the American Society of Clinical Oncology's Genitourinary Cancers Symposium.

The biomarker analysis comes a year after researchers presented the primary results from the randomized Phase II trial, which pitted the VEGF-PARP inhibitor combination against olaparib monotherapy in previously treated mCRPC. The combination, those results showed, led to a significant progression-free survival improvement versus olaparib alone.

At the conference this week, updated results from the overall study population showed that men with mCRPC treated with cediranib and olaparib lived 8.47 months on average without their disease progressing, versus a median progression-free survival of 3.97 months for those treated with the PARP inhibitor alone. As such, the trial met its primary endpoint, but because the study enrolled patients regardless of their HRR status, the researchers wanted to investigate whether this benefit was consistent across all mCRPC patients, or if a specific biomarker-defined group was driving the progression-free survival advantage seen with the combination treatment.

Rana McKay of the University of California, San Diego, one of the investigators who led the trial, said that going into the biomarker analysis she and her team expected the observed progression-free survival benefit would play out in both patients who did and did not harbor HRR gene mutations.

"Given the way that cediranib works [by] inducing a BRCA-like state of down-regulation of HRR genes and making it look like somebody is BRCA deficient … we thought that we would see activity in the homologous recombination proficient patients," McKay said in an interview, explaining that some preclinical work had bolstered this hypothesis.

Cediranib's ability to downregulate HRR genes, in addition to its more straightforward angiogenesis-inhibiting function, were detailed in a 2019 paper in the journal Science Translational Medicine. The authors said that discovering these features revealed a "secret life" for cediranib and that these characteristics may be useful for increasing sensitivity to PARP inhibition.

The HRR status-agnostic benefit that McKay and colleagues hypothesized did not ultimately come to pass in the biomarker analysis, however. Instead, their analysis showed that the benefit was limited to patients with HRR-deficient tumors.

In the study, HRR status was gauged by the BROCA HR assay developed at the University of Washington. Tumors were deemed HRR deficient if they had biallelic loss of one of 10 HRR genes. After testing patients' tissue and blood samples for HRR status, 31 percent of 84 patients in the trial eligible for the biomarker analysis were deemed HRR deficient. This boiled down to 12 patients with HRR deficiency in the arm of the trial receiving the cediranib-olaparib combination and 14 patients with HRR deficiency in the olaparib monotherapy arm.

Looking at clinical outcomes in the HRR-deficient subgroup, McKay and colleagues found that the median progression-free survival among patients on the combination therapy was 10.63 months, versus 3.83 months for those on the monotherapy. But when they looked in the HRR-proficient group of patients, the median progression-free survival in the combination arm — 5.37 months — was not a statistically significant improvement over the monotherapy arm, where the median progression-free survival was 4.03 months.

"We were there expecting there to be a better signal in the proficient group," McKay said. "But we really didn't see this pan out."

While evaluating progression-free survival according to HRR status was a secondary endpoint in the study, the trial wasn't powered to assess responses in subgroups defined by a specific tumor mutation. Patients were either HRR proficient or HRR deficient based on whether they had a mutation in BRCA1, BRCA2, ATM, BARD1, BRIP1, NBN, PALB2, RAD51C, RAD51D, or CDK12.

The researchers did an exploratory analysis in mutation-specific subgroups, however, and found that patients with mutations in BRCA2, CDK12, and ATM appeared to derive greater progression-free survival benefit with the cediranib and olaparib combination over olaparib monotherapy. There were not enough patients with mutations in the other HRR genes to perform the same analysis, but the researchers grouped those patients in an "other" subgroup, and showed that overall they, too, had better progression-free survival with the combination compared to monotherapy.

McKay was careful to emphasize the exploratory nature of this gene-by-gene analysis, and to underscore the single-digit patient numbers in most of these subgroups.

"We really can't make too much of that data because the number of patients in each of those arms is really quite low," she said, adding, however, that the signal's consistency across the different HRD gene mutations could potentially support developing the cediranib-olaparib combination for a broadly HRR-deficient mCRPC patient population.

From a regulatory standpoint, however, it might be important to consider outcomes in specific gene mutation groups. Regulatory bodies diverged in their evaluation of the Phase III PROfound trial data, which led to the approval of olaparib in a biomarker-defined mCRPC population. First, the US Food and Drug Administration approved olaparib for mCRPC patients with an HRR gene mutation, be it in BRCA1/2, ATM, or any of a dozen other HRR genes as determined by Myriad Genetics' BRCAnalysis CDx and Foundation Medicine's FoundationOne CDx. However, in the fall of 2020, the European Medicines Agency's Committee for Medicinal Products for Human Use recommended that olaparib be approved specifically for men with BRCA1/2-mutated mCRPC. The European Commission approved the agent with this narrower indication shortly thereafter. 

McKay cautioned against comparing this cediranib-olaparib trial too directly to PROfound, since the patient populations differed. Patients enrolled in the cediranib-olaparib trial had almost all received prior chemotherapy, whereas patients in PROfound only received prior hormonal therapy. The trials also differed importantly in their comparator arms, with the cediranib-olaparib treatment being compared to olaparib, while in PROfound, olaparib was compared to antiandrogen medications.

In terms of next steps for the cediranib-olaparib combination, McKay said she and her colleagues are eager to conduct a larger study "probably in a biomarker-selected patient population." Specifically, they would evaluate the combination in patients with any HRR gene mutation.

However, this next step will require, as all larger trials do, an increase in support and funding, which isn't a sure thing given cediranib's track record so far. The agent has consistently failed to meet its primary endpoints in clinical trials — particularly in the setting of ovarian cancer — and AstraZeneca has taken steps such as withdrawing regulatory filing in Europe, albeit for a different indication.

"It's not clear what the right avenue is for moving that study forward," she said. "Is it going to be through the cooperative groups? Is it going to be through an industry-sponsored trial? Cediranib has been around for a long time … I think it's coming off patent soon." The Phase II mCRPC trial, of note, was conducted through the National Cancer Institute's Experimental Therapeutics Clinical Trials Network (ETCTN) and supported by the NCI and Prostate Cancer Foundation, though AstraZeneca and Merck did supply the agents.

The uncertainty about the combo's next step is rooted in part in the fact that after showing an initial benefit versus olaparib monotherapy in ovarian cancer, it did not meet its primary endpoint in a subsequent Phase III trial.

Prostate cancer is a different story, though. "Biologically, they're different diseases," said McKay. "There is a track record for some efficacy of VEGF inhibition in prostate cancer, but there's been no agent to date that has demonstrated a benefit in overall survival in the CRPC setting."

This may change, depending on how additional studies of this combination are designed, should the combo move forward. Ultimately, McKay said, this decision may very well be in the hands of industry partners like AstraZeneca.