Metastatic castration-resistant prostate cancer remains a challenging disease after progression on docetaxel-based chemotherapy. While immune checkpoint inhibitors have changed treatment across several cancers, their role in prostate cancer has been more limited, partly because prostate cancer often has a lower tumor mutational burden and a less inflamed tumor microenvironment compared with other tumor types.
The randomized portion of the phase 2 CheckMate 650 trial provides new insight into the use of dual immune checkpoint blockade in this setting. The study evaluated different dosing regimens of nivolumab plus ipilimumab, ipilimumab monotherapy, and cabazitaxel in patients with chemotherapy-refractory metastatic castration-resistant prostate cancer. The results showed that nivolumab plus ipilimumab had antitumor activity in a subset of patients, including durable responses, while also highlighting the continued need for better biomarkers to identify patients most likely to benefit.
The article, titled “Nivolumab plus ipilimumab for chemotherapy-refractory metastatic castration-resistant prostate cancer: results from the randomized portion of the phase 2 CheckMate 650 trial,” was available as an Article in Press in Nature Communications in 2026. The manuscript was provided as an unedited version for early access and was expected to undergo further editing before final publication.
Authors: The study was authored by Padmanee Sharma, Michael Krainer, Fred Saad, Daniel Castellano, Jens Bedke, Mariusz Kwiatkowski, Akash Patnaik, Giuseppe Procopio, Paweł Wiechno, Samith Kochuparambil, Christian Thomas, José Ángel Arranz Arija, Steven L. McCune, Steinbjørn Hansen, Gedske Daugaard, Juan Ignacio Delgado Mingorance, Craig Kukard, Sumit K. Subudhi, Sreyashi Basu, Sonali Jindal, Bilal A. Siddiqui, Ana Lako, Saurabh Gupta, Viktor Fedorov, Neha P. Amin, Arancha Campos, Yumeng Wang, Justin M. David, and Russell K. Pachynski.
Study design
CheckMate 650 was an international, open-label, multicohort phase 2 trial. The randomized portion included 259 biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer. Patients had previously received docetaxel-containing therapy and had disease progression before enrollment.
Patients were randomized to one of four treatment cohorts. The first cohort received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for up to four doses, followed by nivolumab maintenance. The second cohort received nivolumab 1 mg/kg every 3 weeks plus ipilimumab 3 mg/kg every 6 weeks, followed by nivolumab maintenance. The third cohort received ipilimumab monotherapy, and the fourth cohort received cabazitaxel with prednisone or prednisolone.
The primary endpoints were objective response rate and radiographic progression-free survival. Key secondary endpoints included overall survival, PSA response rate, and safety. Importantly, the randomized portion of the trial was not designed to statistically compare outcomes between cohorts, so the results should be interpreted descriptively rather than as direct evidence of superiority between treatments.
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Efficacy results
Among patients with measurable disease at baseline, objective response rates were 9.3% with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, 19.5% with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 4.5% with ipilimumab monotherapy, and 12.2% with cabazitaxel.
Complete responses were reported only in the nivolumab plus ipilimumab cohorts. One patient achieved a complete response in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort, and two patients achieved complete responses in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort. Median time to objective response was approximately 2 months in both nivolumab plus ipilimumab cohorts, and median duration of objective response was not reached in either cohort.
Confirmed PSA response rates were 13.8%, 18.2%, 5.4%, and 23.9% in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, ipilimumab monotherapy, and cabazitaxel cohorts, respectively. Median duration of confirmed PSA response was not reached in either nivolumab plus ipilimumab cohort.
Median radiographic progression-free survival was 3.9 months with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, 4.2 months with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 3.5 months with ipilimumab monotherapy, and 7.9 months with cabazitaxel.
After a median follow-up of 23.3 months for overall survival, median overall survival was 15.9 months, 13.5 months, 18.5 months, and 14.8 months, respectively. However, these survival outcomes should be interpreted carefully because the study was not powered for cross-cohort comparisons, baseline characteristics differed between cohorts, and patients in the ipilimumab monotherapy and cabazitaxel cohorts were allowed to cross over to nivolumab plus ipilimumab after disease progression.
Safety
Treatment-related adverse events of any grade occurred in 75.3% of patients receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, 79.5% receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 71.1% receiving ipilimumab monotherapy, and 80.6% receiving cabazitaxel.
Grade 3 or higher treatment-related adverse events occurred in 28.8%, 30.1%, 18.4%, and 34.7% of patients, respectively. In the nivolumab plus ipilimumab cohorts, the most common high-grade treatment-related adverse events were mainly gastrointestinal or immune-mediated, including diarrhea, colitis, immune-mediated enterocolitis, hypophysitis, and increased lipase. In the cabazitaxel cohort, the most common high-grade treatment-related adverse events were mainly hematologic, including anemia, decreased neutrophil count, neutropenia, and febrile neutropenia.
Treatment-related adverse events led to discontinuation in 15.1% of patients in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort, 26.0% in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, 7.9% in the ipilimumab monotherapy cohort, and 8.3% in the cabazitaxel cohort.
Two deaths were considered related to study drug toxicity. One patient in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort died due to immune-mediated pneumonitis, and one patient in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort died due to immune-mediated colitis.
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Biomarker analysis
The study also explored potential biomarkers of response. Tumor mutational burden was evaluated using both tumor tissue and blood samples. In the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort, higher tissue or blood tumor mutational burden was associated with numerically higher response rates in some analyses. However, this relationship was not consistent across all cohorts or endpoints, and the authors noted that there is no established high tumor mutational burden threshold in metastatic castration-resistant prostate cancer.
A separate exploratory post hoc analysis used CODEX spatial proteomics to study the tumor microenvironment in pretreatment tumor samples from a small subset of patients treated with immunotherapy. Researchers identified perivascular immune niches comprising CD31-positive blood vessels surrounded by CD14-positive myeloid cells, CD4-positive and CD8-positive T cells, and CD11c-positive dendritic cells. These niches were more frequent in pretreatment primary prostate tumors from responders than nonresponders.
The investigators also developed a transcriptional signature derived from these immune niches and tested it in the TCGA-PRAD dataset. High expression of this signature was reported by the authors to be associated with prolonged overall survival, though they describe this as an exploratory, hypothesis-generating finding requiring confirmation.
Conclusion
The randomized portion of CheckMate 650 adds important evidence on the use of nivolumab plus ipilimumab in chemotherapy-refractory metastatic castration-resistant prostate cancer. The combination did not show broad activity across the entire study population, and median radiographic progression-free survival remained short. However, some patients experienced deep and durable responses, including complete responses, suggesting that dual immune checkpoint blockade may have clinical activity in selected patients.
The study also highlights one of the central challenges in prostate cancer immunotherapy: identifying who is most likely to benefit. Tumor mutational burden alone may not be sufficient, while the exploratory findings around perivascular immune niches suggest that features of the tumor microenvironment could become important for future biomarker development.
Overall, CheckMate 650 supports continued investigation of immunotherapy-based strategies in selected patients with metastatic castration-resistant prostate cancer. Future studies will need to validate tissue and liquid biopsy biomarkers prospectively to improve patient selection and better define the role of nivolumab plus ipilimumab in this disease setting.
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