Ciforadenant Has Promising Anti-tumor Activity in mCRPC, Early Data Show

Ciforadenant Has Promising Anti-tumor Activity in mCRPC, Early Data Show
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Treatment with Corvus Pharmaceuticalsciforadenant (CPI-444), alone or in combination with Tecentriq (atezolizumab), is well tolerated and showed promising anti-tumor activity in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) patients, early data from a Phase 1b/2 clinical trial suggest.

Lawrence Fong, MD, leader of the cancer immunotherapy program at the  Helen Diller Family Comprehensive Cancer Center at the University of California San Francisco, presented the findings at the American Society of Clinical Oncology (ASCO) 2020 Genitourinary Cancers Symposium.

The poster presentation was titled, “Adenosine Receptor Blockade with Ciforadenant ± Atezolizumab in Advanced Metastatic Castration Resistant Prostate Cancer (mCRPC).”

CD73 is a cell surface protein that is often elevated in metastatic prostate cancer patients and helps the tumor grow by dampening anti-tumor immune responses. It does so by increasing the levels of adenosine, an immunosuppressive metabolite.

Adenosine works much like other immune checkpoints, such as PD-L1 and CD47, signaling through a receptor on immune cells and starting a chain of events that “tell” immune cells to leave the cancer unharmed. Therapies blocking these molecules on cancer cells or their receptors on immune cells — broadly called immune checkpoint inhibitors — are now a mainstay in cancer therapy.

Researchers at Corvus have been developing molecules that block adenosine signaling in multiple cancers. Ciforadenant, in particular, is an inhibitor of the adenosine A2A receptor (A2AR) on immune cells.

The investigational therapy is being studied, alone and in combination with Genentech’s Tecentriq, in people with renal cell cancer and mCRPC patients in a randomized, open-label Phase 1b/2 trial (NCT02655822).

Tecentriq is another immune checkpoint inhibitor, designed to block the PD-L1 protein, which is also produced by cancer cells as a mechanism to evade anti-tumor immune responses.

The trial’s main goals are to determine ciforadenant’s safety — assessed through the number of dose-limiting toxicities and treatment-related adverse events — as well as the proportion of patients who responded to treatment, and measures of ciforadenant’s behavior once inside the body.

Researchers are also assessing whether a panel of genes of the adenosine pathway called adenosine signature is able to predict patients most likely to respond to ciforadenant.

“Our recently published adenosine signature allows us to identify tumors where adenosine is playing an immunosuppressive role and where adenosine blockade may be clinically useful,” Corvus CEO Richard Miller, MD, said in a press release.

Fong presented the results from 35 patients with advanced mCRPC who failed to respond to a median of three prior therapies. Eleven of them received oral, twice-daily ciforadenant only, and 24 were treated with ciforadenant plus Tecentriq, given as an into-the-vein infusion every two weeks.

Almost half (43%) had metastases in the abdomen, a negative prognostic factor for patients with mCRPC.

After a median follow-up of 3.2 months, one patient had a partial response, and his levels of prostate specific antigen (PSA) — a biomarker of prostate cancer — dropped from 98 ng/mL to less than 1 ng/mL.

Ten other patients also showed signs of tumor regression, although not enough to achieve the requirement for partial response. Seven have achieved stable disease lasting more than six months. One of these patients remains on therapy.

Five patients have yet-unconfirmed stable disease and continue on therapy. In total, nine patients are still getting treatment.

Gene profiling of tumor biopsies showed a significant correlation between the levels of CD73 in the tumor with the adenosine signature, supporting a role for CD73 and adenosine-regulated genes in prostate cancer.

Treatment was well tolerated, with only one patient in the ciforadenant group experiencing severe fatigue, and one in the combination group reporting severe anemia.

“We are pleased to see activity in mCRPC both with ciforadenant monotherapy and in combination with atezolizumab,” said Miller. “The results from this study and prior results reported with CPI-006, our anti-CD73 antibody, indicate that prostate cancer is another potential disease that is amenable to therapy with adenosine blockade. Many prostate cancers express CD73 and contain adenosine that is produced by multiple biochemical sources.”

“We plan to pursue the mCRPC indication further, and we anticipate additional data to be presented at the ASCO annual meeting in late May/June,” he said. “Overall, these results continue to demonstrate our leading position in the development of agents targeting the adenosine pathway.”

The study is still recruiting participants. More information on enrollment is available on the trial’s page.

Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.
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Inês holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in blood vessel biology, blood stem cells, and cancer. Before that, she studied Cell and Molecular Biology at Universidade Nova de Lisboa and worked as a research fellow at Faculdade de Ciências e Tecnologias and Instituto Gulbenkian de Ciência. Inês currently works as a Managing Science Editor, striving to deliver the latest scientific advances to patient communities in a clear and accurate manner.
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Patricia holds a Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She has also served as a PhD student research assistant at the Department of Microbiology & Immunology, Columbia University, New York.
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