Combination therapy may improve immune response against advanced prostate cancer

by Melissa Rohman, Northwestern University

edited by Gaby Clark, reviewed by Andrew Zinin

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Combining the targeted therapy olaparib with an additional immunotherapy may improve immune response in a subgroup of patients with metastatic castration-resistant prostate cancer who responded poorly to initial treatment, according to a Northwestern Medicine study published in The Journal of Clinical Investigation.

"We identified a new combination therapy strategy to overcome immune-cold tumors and sensitize them to immunotherapy," said Bin Zhang, MD, Ph.D., the Johanna Dobe Professor of Cancer Immunology, who was senior author of the study.

Metastatic castration-resistant prostate cancer is an advanced form of prostate cancer that has spread beyond the prostate and no longer responds to hormone therapy. It is a leading cause of cancer-related mortality in men worldwide, with an average life expectancy of three years, highlighting an urgent need for more effective and targeted treatment strategies.

Treatment options for managing the disease and extending life expectancy may include a combination of surgery, chemotherapy, immunotherapy or radiation therapy.

Approximately 30% of patients with metastatic castration-resistant prostate cancer who have homologous recombination repair (HRR) deficiencies—which occur when a cell loses its ability to repair broken double-stranded DNA—may also respond to poly (ADP-ribose) polymerase inhibitors, or PARP inhibitors. These medications block enzymes in cancer cells that help repair breaks in DNA and prevent cancer cell proliferation.

However, previous clinical trials that evaluated the efficacy of combining the PARP inhibitor olaparib with PD-1/PD-L1 inhibitors—immune checkpoint inhibitors that help the immune system better recognize and attack cancer cells—have shown poor results.

In the current study, Zhang's team aimed to identify the mechanisms by which PARP inhibitors modulate immune responses in metastatic castration-resistant prostate cancer cells.

First, the scientists performed bulk RNA sequencing on mouse prostate cancer cells with HRR deficiencies that were treated with olaparib.

Subsequent transcriptomic analysis of the olaparib-treated cells revealed an upregulation of CD73, an immune checkpoint enzyme that produces adenosine to suppress T-cell activation.

The scientists also discovered that olaparib-driven CD73 upregulation was mediated through the ATR–CHEK1–IRF1 and TGF-β1–AKT signaling pathways, both of which respond to DNA damage and activate DNA repair.

Lastly, they found that combining olaparib with a CD73 blockade therapy in prostate cancer mouse models with HRR proficiency and knockout of the tumor suppressor gene PTEN delayed tumor growth, improved T-cell infiltration and enhanced CD8⁺ T-cell function.

The findings suggest that combination treatment with olaparib and CD73 blockade therapy may improve overall treatment response in patients with metastatic castration-resistant prostate cancer, even without HRR deficiencies.

"These findings provide mechanistic insight into how prostate cancer cells respond to DNA damage stress and highlight CD73 as a therapeutically actionable target to improve the efficacy of olaparib-based therapies," said Zhang, who is also a professor of medicine in the Division of Hematology and Oncology, of Microbiology-Immunology and of Pathology.

Ping Xie, Ph.D., research assistant professor of medicine in the Division of Hematology and Oncology, was a leading co-first author of the study.

Publication details

Ping Xie et al, CD73 inhibition overcomes adaptive immune resistance to PARP inhibiton in models of prostate cancer, Journal of Clinical Investigation (2026). DOI: 10.1172/jci203785

Journal information: Journal of Clinical Investigation

Key medical concepts

Metastatic Castration-Resistant Prostate Carcinomaolaparib5'-NucleotidaseHomologous Recombination Deficiency

Clinical categories

OncologyUrologyMen's health Provided by Northwestern University Who's behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news. Full profile →

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