Nat Commun
Immune signature flags prostate cancer responders to combo treatment
Clinical takeaway: Combination immunotherapy produced deep, durable responses in a subset of men with chemotherapy-refractory metastatic prostate cancer, though response rates were modest overall. A candidate tissue biomarker may help identify likely responders, but it requires validation.
Men with metastatic castration-resistant prostate cancer that has progressed through chemotherapy have few effective options. Combination checkpoint inhibition has shown signals of activity in earlier work but with substantial toxicity, raising the question of whether better dosing or patient selection could make the approach viable. The randomized portion of the study tested two alternative immunotherapy regimens against ipilimumab alone and standard chemotherapy. It also looked for tissue features that distinguished patients who responded from those who didn't.
Among 259 randomized patients, the two combination immunotherapy cohorts produced objective response rates of 9.3% and 19.5%, with three complete responses in the combination arms. Responses were notable for their depth and durability: most responders had large reductions in tumor size and PSA, and median duration of response hadn't been reached in either combination arm at data cutoff. Ipilimumab alone produced a 4.5% response rate, and cabazitaxel produced 12.2%. The trial wasn't designed for direct cohort comparisons, and response rates in the combination arms fell below the 30% the trial was designed to detect.
To understand why some patients had exceptional responses, researchers performed spatial proteomic profiling on pre-treatment tumor samples from 12 patients who received immunotherapy. They identified clusters of immune cells, including myeloid cells, T cells, and dendritic cells, organized around blood vessels in what the authors called perivascular immune niches. These niches were significantly denser in responders than in non-responders.
A transcriptional signature derived from genes expressed in these niches was then tested in 484 prostate cancer patients from The Cancer Genome Atlas, where higher signature expression was associated with prolonged overall survival.
The biomarker analysis was based on only 12 patients, and the validation cohort had not received immunotherapy. The signature needs testing in larger groups of immunotherapy-treated patients before it can guide treatment decisions.
"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, MD, PhD, professor of genitourinary medical oncology and immunology at The University of Texas MD Anderson Cancer Center and the study's principal investigator.
Source: Sharma P. Nat Commun. 2026 May 20. Nivolumab plus ipilimumab for chemotherapy-refractory metastatic castration-resistant prostate cancer: results from the randomized portion of the phase 2 CheckMate 650 trial