Results from a phase II trial led by researchers at The University of Texas MD Anderson Cancer Center suggest that a combination of ipilimumab (anti–CTLA-4) plus nivolumab (anti–PD-1) can generate durable responses in a subset of patients with metastatic castration-resistant prostate cancer, an immune-cold cancer that does not typically respond well to immunotherapy.1
In a cohort of patients without previous chemotherapy treatment, the overall response rate was 25% and median overall survival was 19 months. In a postchemotherapy cohort, the overall response rate was 10% and median overall survival was 15.2 months. Four patients (two in each cohort) achieved a complete response.
The results of the CheckMate 650 trial, published in Cancer Cell, are the first report of combination immune checkpoint inhibitors in metastatic castration-resistant prostate cancer.1 Early results from this study were presented at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium. Based on the findings, alternate dosing regimens are now being evaluated in an expanded clinical trial to reduce treatment-related toxicities.
Padmanee Sharma, MD, PhD
“Historically, prostate cancer has been very resistant to checkpoint inhibitors because it is immunologically cold with few tumor-infiltrating T cells,” said principal investigator Padmanee Sharma, MD, PhD, Professor of Genitourinary Medical Oncology and Immunology. “These results suggest that a combination approach to increase T cell infiltration and then block inhibitory pathways may be a useful strategy for treating these patients. Going forward, we plan to optimize the schedule and dosing to improve the safety profile.”
Designing a Combination Strategy
In previous research published in Nature Medicine, Dr. Sharma and colleagues discovered that prostate cancers deploy multiple mechanisms to dampen the antitumor immune response.2 Although anti–CTLA-4 therapy could recruit T cells, the tumor-infiltrating T cells elicited compensatory inhibitory pathways, including immune-suppressing proteins PD-L1 and VISTA.
This would explain why previous clinical trials evaluating single-agent checkpoint inhibitors have not been effective in treating patients with metastatic castration-resistant prostate cancer, said Dr. Sharma, who co-directs MD Anderson’s immunotherapy platform, part of the institution’s Moon Shots Program.
The researchers hypothesized that combining anti–CTLA-4 (ipilimumab) with anti–PD-1 (nivolumab) may be effective in bringing T cells into the tumor and overcoming the resulting immunosuppressive response.
The multi-institution, open-label study enrolled 90 men with metastatic castration-resistant prostate cancer, who received the combination therapy every three weeks. Patients were enrolled in two cohorts, one with and one without prior chemotherapy. Participants were 77.8% White, 10% Black/African-American, and 12.2% other.
In addition to response rates, the combination therapy achieved disease control in 46.9% and 13.3% of patients, with a median progression-free survival of 5.5 and 3.8 months in the prechemotherapy and postchemotherapy cohorts, respectively.
Despite the positive responses, grade 3 and 4 treatment-related adverse events occurred in 42.2% of prechemotherapy patients and in 53.3% of postchemotherapy patients. The most common of these events were diarrhea, pneumonitis, colitis, and increased lipase. Treatment-related adverse events led to discontinuation of therapy in a total of 31 patients. There were four treatment-related deaths, two in each cohort.
“There were patients who had clear benefit as a result of treatment, but there also were patients who had serious adverse events, which led us to amend the protocol to evaluate alternate schedules and doses and improve the safety of this approach,” said Dr. Sharma.
Based on these data, the trial has been expanded to include more than 400 patients, with different dosing and schedules to identify strategies that can improve efficacy and minimize toxicities.
Exploring Biomarkers Associated With Response
The research team also conducted analyses to identify potential biomarkers associated with clinical outcomes in these patients.
Although this study represents a small number of patients, its findings suggest that the combination may be more effective in patients with a relatively high tumor mutational burden. This is consistent with previous work that suggests certain patients with the disease may respond to checkpoint blockade despite having low tumor mutational burden relative to other cancers, such as melanoma and lung cancer.
“The current study represents the first step in trying to identify metastatic castration-resistant prostate cancer patients who would benefit from combination therapy with ipilimumab plus nivolumab based on chemotherapy exposure as well as preliminary biomarker analyses,” said co-author Sumit Subudhi, MD, PhD, Assistant Professor of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center. “The data generated to date are encouraging, but we clearly have more work to do in the expansion cohort as we try to administer effective combination strategies with fewer toxicities.”
Disclaimer: This study was supported by Bristol-Meyers Squibb and ONO Pharmaceutical Company, Limited. Dr. Sharma is a member of the Parker Institute for Cancer Immunotherapy (PICI) and codirector of PICI at MD Anderson.
1. Sharma P, Pachynski RK, Narayan V, et al: Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: Preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. September 10, 2020 (early release online).
2. Gao J, Ward J. Pettaway C, et al: VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Nat Med 23:551-555, 2017.