A new discovery could help doctors predict which patients with advanced, treatment-resistant prostate cancer will benefit from a powerful combination of immunotherapy drugs, rather than subjecting all patients to the same approach. Researchers at the University of Texas MD Anderson Cancer Center identified a specific gene expression pattern in tumors that signals which patients are most likely to experience lasting benefits from combined immune checkpoint inhibitors.

What Is This New Biomarker and Why Does It Matter?

The study, published in Nature Communications, analyzed results from the CheckMate 650 trial, which tested a combination of two immunotherapy drugs called ipilimumab and nivolumab in patients with metastatic castration-resistant prostate cancer (mCRPC), a form of the disease that has stopped responding to standard hormone therapy and chemotherapy. The research team examined tumor tissue samples from patients who had exceptional responses to the treatment and discovered clusters of specific immune cells present at higher density in those patients' tumors. They then identified a signature showing high expression of particular genes within these immune cell clusters.

"These findings provide evidence that combination immunotherapy has the potential to benefit certain patients with treatment-resistant advanced prostate cancer, a disease with high unmet medical need," said Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology at the Allison Institute.

Padmanee Sharma, M.D., Ph.D., Professor of Genitourinary Medical Oncology and Immunology, University of Texas MD Anderson Cancer Center

This biomarker could allow doctors to analyze a patient's tumor before treatment begins to determine whether they are likely to respond well to this combination therapy or whether they should explore alternative treatment options instead. This precision approach could spare patients from enduring side effects of a treatment that may not work for them.

What Were the Trial Results?

The randomized portion of the CheckMate 650 trial enrolled 259 patients with mCRPC who had developed resistance to prior chemotherapy. Participants were assigned to one of four treatment cohorts that tested two different dosing variations of the combination immunotherapy, ipilimumab alone, or standard chemotherapy. The immunotherapy combinations achieved response rates of 9.3% and 19.5%, with three complete responses across the two cohorts. While these overall response rates may seem modest, a subset of patients experienced notable responses marked by significant tumor shrinkage, declined prostate-specific antigen (PSA) levels, and prolonged overall survival.

Treatment-related side effects of grade 3 or higher occurred in 18.4% to 34.7% of patients across the different treatment cohorts. The most common adverse effects included diarrhea, enterocolitis (inflammation of the small intestine and colon), and hypophysitis (inflammation of the pituitary gland). There were two treatment-related deaths during the study.

How Could This Advance Prostate Cancer Care?

The discovery of this immune signature represents an important step toward personalized cancer medicine. Rather than offering the same treatment to all patients with advanced prostate cancer, doctors could use this biomarker to identify which patients are most likely to benefit from combination immunotherapy before treatment begins. This approach aligns with a broader trend in cancer care toward matching patients with treatments based on their individual tumor characteristics.

"This study reinforces the utility of our approach to better understand the tumor-immune microenvironment in order to better identify patients that could benefit from immunotherapy," Sharma explained.

Padmanee Sharma, M.D., Ph.D., Professor of Genitourinary Medical Oncology and Immunology, University of Texas MD Anderson Cancer Center

What Are the Next Steps for This Research?

The combination of ipilimumab and nivolumab studied in this trial remains investigational and has not yet been approved by the Food and Drug Administration. Future studies will seek to confirm this biomarker and treatment approach in larger, prospective patient cohorts to validate the findings and determine how broadly this signature applies across different patient populations.

Steps to Understanding Your Prostate Cancer Treatment Options

• Know Your Risk Factors: African American men and those with a family history of prostate cancer face higher risk and should discuss screening and monitoring with their doctor starting at age 40 or 45.
• Seek a Second Opinion: If you receive a prostate cancer diagnosis, getting a second opinion from a specialized urologic oncologist can help ensure you understand all available treatment options, from observation to surgery to radiation to immunotherapy.
• Ask About Biomarkers: When discussing advanced prostate cancer treatment, ask your doctor whether biomarker testing of your tumor could help predict which treatments are most likely to work for your specific cancer.
• Discuss Clinical Trials: If standard treatments have not worked, ask whether you might be eligible for clinical trials testing newer combinations like the immunotherapy approaches being studied in trials like CheckMate 650.

The discovery of this new biomarker offers hope to patients with advanced prostate cancer who have exhausted standard treatment options. By identifying which patients are most likely to benefit from combination immunotherapy, this research could help doctors make more informed treatment decisions and improve outcomes for those living with this challenging disease.