Oncology · Medical Literature
Randomized phase II trial of nivolumab and ipilimumab with or without stereotactic body radiation therapy in patients with metastatic castration-resistant prostate cancer: the CheckPRO, CA209-8TY trial.
Abstract
Metastatic castration-resistant prostate cancer (mCRPC) is among the leading causes of cancer-related mortality in men worldwide. Treatment options for mCRPC typically include chemotherapy and androgen receptor pathway inhibitors. Immune checkpoint inhibitors (ICIs) have demonstrated a limited effect in mCRPC. We hypothesized that the addition of stereotactic body radiation therapy (SBRT) could enhance immune responses and improve treatment outcomes. Patients with mCRPC who had received at least two prior lines of therapy were randomized 1:1 to receive SBRT with nivolumab and ipilimumab (arm A) or nivolumab and ipilimumab (arm B). The dual primary endpoints in the study were prostate-specific antigen (PSA) response rate and objective response rate (ORR). Secondary endpoints included overall survival (OS), PSA, radiologic progression-free survival, and toxicity. We enrolled 91 patients, and 81 patients received at least one treatment with ICIs and were eligible for evaluation of the efficacy and safety endpoints. Of the evaluable patient population, the confirmed PSA response rate was 21.6% (95% CI 9.8% to 38.2%) in arm A, and 20.5% (95% CI 9.8% to 35.3%) in arm B. ORR was 16.7% (95% CI 4.7% to 37.4%) and 22.2% (95% CI 10.1% to 39.2%) in arms A and B, respectively. Median OS was 10.2 months (95% CI 7.1 to 15.2) in arm A and 9.2 months (95% CI 7.1 to 14.4) in arm B. Treatment-related adverse events grade 3-4 were observed in 27 patients (33.3%). The addition of SBRT to nivolumab and ipilimumab did not improve outcomes; however, a fraction of the patients had a response to the treatment combination of nivolumab and ipilimumab. Explorative translational research is needed to identify possible biomarkers of response to immunotherapy with ICIs in mCRPC. European Union Clinical Trial Registry (https://www.clinicaltrialsregister.eu) EudraCT number: 2018-003461-34 and on https://clinicaltrials.gov (NCT05655715).
Clinical relevance
Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer mortality in men, with limited efficacy demonstrated by immune checkpoint inhibitors (ICIs) in this setting. This randomized phase II trial addresses the clinically important question of whether stereotactic body radiation therapy (SBRT) can serve as an in situ vaccine to potentiate anti-tumor immunity and augment ICI efficacy in heavily pre-treated mCRPC patients. The findings are immediately relevant to oncologists considering combination immunotherapy strategies in a population that has exhausted standard androgen receptor pathway inhibitors and chemotherapy.
Key findings
1. PSA response rate was 21.6% (95% CI 9.8%–38.2%) in the SBRT + nivolumab/ipilimumab arm (Arm A) versus 20.5% (95% CI 9.8%–35.3%) in the nivolumab/ipilimumab alone arm (Arm B) — no statistically significant difference between arms. 2. Objective response rate (ORR) was 16.7% (95% CI 4.7%–37.4%) in Arm A and 22.2% (95% CI 10.1%–39.2%) in Arm B, again favoring no additive benefit from SBRT. 3. Median overall survival was 10.2 months (95% CI 7.1–15.2) in Arm A versus 9.2 months (95% CI 7.1–14.4) in Arm B, with overlapping confidence intervals indicating no meaningful OS benefit with the addition of SBRT. 4. Grade 3–4 treatment-related adverse events occurred in 27 of 81 evaluable patients (33.3%), reflecting a clinically significant immune-related toxicity burden with dual ICI therapy regardless of SBRT addition. 5. A total of 91 patients were enrolled and 81 were evaluable for efficacy and safety, all having received at least two prior lines of therapy — confirming this was a heavily pre-treated, high-risk population. 6. No NNT/NNH or formal statistical comparison p-values between arms were reported in the abstract; the trial did not meet its dual primary endpoints of improved PSA response rate or ORR with the addition of SBRT.
Practice implications
The addition of SBRT to dual ICI therapy (nivolumab + ipilimumab) should not be adopted as a standard strategy to enhance immunotherapy responses in mCRPC, as this trial demonstrates no improvement in PSA response rate, ORR, or overall survival with this combination in patients who have received at least two prior lines of therapy. Clinicians should nonetheless note that a meaningful subset of mCRPC patients (~20–22%) do respond to nivolumab and ipilimumab alone, underscoring the urgent need for predictive biomarker development — such as tumor mutational burden, microsatellite instability, or CDK12 alteration profiling — to identify which patients are most likely to benefit from ICI-based regimens. Given the 33.3% rate of grade 3–4 treatment-related adverse events, careful patient selection, baseline performance status assessment, and proactive immune-related adverse event monitoring protocols are essential when considering dual ICI therapy in this population.