New gene expression signature may guide immunotherapy for resistant prostate cancer patients

Researchers with the James P. Allison Institute™ at The University of Texas MD Anderson Cancer Center have discovered a new gene expression signature within tumors that can help identify patients with metastatic castration-resistant prostate cancer (mCRPC) who are more likely to experience lasting benefits from combined immunotherapy treatment.

Results from the Phase 2 CheckMate 650 trial, published in Nature Communications, demonstrate that the investigational combination of immune checkpoint inhibitors ipilimumab and nivolumab achieved antitumor responses in a subset of patients with chemotherapy-resistant disease. Using the unique capabilities of the Allison Institute's immunotherapy platform, researchers discovered an immune signature linked with prolonged overall survival, which has the potential to help physicians identify who would be most likely to benefit from this combination.

The study was led by principal investigator Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology, vice president of Immunobiology, and director of scientific programs for the Allison Institute.

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. 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."

Padmanee Sharma, M.D., Ph.D., Professor of Genitourinary Medical Oncology and Immunology, vice president of Immunobiology, and director of scientific programs, Allison Institute

What are the key results of this trial?

The randomized portion of this trial enrolled 259 patients with mCRPC who had developed resistance to prior chemotherapy. Participants were assigned to one of four treatment cohorts evaluating two dosing variations of the combination immunotherapy, ipilimumab alone, or standard-of-care chemotherapy. The study was not designed for comparisons between cohorts.

The immunotherapy cohorts achieved response rates of 9.3% and 19.5%, with three complete responses across the two cohorts. A subset of patients had notable responses, marked by significant tumor shrinkage, declined prostate specific antigen (PSA) levels and prolonged overall survival.

Treatment-related adverse events of grade 3 or higher occurred in 18.4-34.7% of patients across cohorts. The most common side effects were diarrhea, enterocolitis and hypophysitis. There were two treatment-related deaths during the study.

How can this new biomarker improve treatments for these patients?

To understand why a subset of patients had benefitted most from this investigational combination, the researchers evaluated pre-treatment tissue samples from tumors with and without an exceptional response.

Using the Allison Institute's immunotherapy platform, the researchers performed spatial profiling of these samples and identified clusters of particular immune cells present at higher density in patients with exceptional responses. Further, they identified a signature indicating high expression of specific genes within these niches.

By using these features as a biomarker, researchers may be able to analyze tumors prior to treatment to determine if a patient is likely to benefit from the combination immunotherapy or if alternate treatments should be explored.

Despite modest response rates overall, these results suggest that certain patients with chemotherapy-resistant mCRPC may benefit from combination immunotherapy. The combination 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 cohorts.