Combining the targeted therapy olaparib with a supplemental 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, PhD, 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 away from the prostate and no longer responds to hormone therapy. It’s 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 percent of patients with metastatic castration-resistant prostate cancer who have homologous recombination repair (HHR) deficiencies — which occurs when a cell loses its ability to fix 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 have 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 the 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 driven 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 proficiencies and knockout of the tumor suppressor gene PTEN delayed tumor growth, improved T-cell infiltration and enhanced CD8+ T-cell function.
The findings suggest a combination treatment of olaparib plus 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, PhD, research assistant professor of Medicine in the Division of Hematology and Oncology, was a leading co-first author of the study.
Co-authors include Timothy Kuzel, MD, clinical professor of Medicine in the Division of Hematology and Oncology; Deyu Fang, PhD, the Hosmer Allen Johnson Professor of Pathology; Weiguo Cui, PhD, professor of Pathology in the Division of Experimental Pathology; Jennifer Wu, PhD, the Mary and Patrick Scanlan Professor of Urology and of Microbiology-Immunology; and Sarki Abdulkadir, MD, PhD, the John T. Grayhack, MD, Professor of Urological Research.
Zhang, Fang, Cui, Wu and Abdulkadir are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Zhang, Fang, Cui and Wu are also members of the Center for Human Immunobiology.
This work was supported by National Institute of Health grants CA290743, CA258857 and SPORE funding (P50CA180995).
