The addition of nivolumab (Opdivo) to standard-of-care (SOC) radiation and androgen deprivation therapy (ADT) led to disease control in patients with high-volume grade group 5 (GG5) prostate cancer, including those with oligometastatic disease, according to results from a phase 2 trial (NCT03543189) published in the Journal for ImmunoTherapy of Cancer.1
Among evaluable patients (n = 31), the 2-year freedom from biochemical recurrence (FFBR) rate was 90.3% (95% CI, 74.3%-98.0%), exceeding the prespecified historical control rate of 75% (1-sided P = .024) and meeting the study’s primary end point. The median FFBR was not reached.
"Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 [prostate cancer] population and may represent a promising therapeutic intensification strategy," Kosj Yamoah, MD, PhD, chairman and senior member of the Department of Radiation Oncology at H. Lee Moffitt Cancer Center, as well as director of radiation oncology global health records and professor of oncological sciences at USF Morsani College of Medicine, in Tampa, Florida, wrote in the publication.
Key Takeaways From the Phase 2 Study
- Adding nivolumab to SOC radiation and hormone therapy was associated with a 2-year FFBR of 90.3% (95% CI, 74.3%-98.0%) in patients with high-volume grade group 5 prostate cancer.
- Definitive and probable nivolumab-related toxicity included grade 2 and grade 3 acute AEs in 6.3% of patients each, with no grade 4 or higher AEs reported.
- Ricketts Immunosuppression Score was identified as a potential predictive biomarker, with high scores independently associated with early pathological response and complete radiographic response, and low scores independently associated with increased risk of metastatic progression on multivariable analysis (HR, 9.256; P = .044).
What was the rationale for the phase 2 trial?
GG5 prostate cancer carries a significantly worse prognosis compared with lower Gleason grade groups and is an independent risk factor for recurrence among patients with high-risk and very high-risk disease (P = 0.016). Patients with localized GG5 PCa treated with high-dose external beam radiation therapy (EBRT) and long-term ADT face a 5-year biochemical recurrence rate of 27% and a metastatic failure rate of 24%, highlighting the need for more effective therapeutic strategies.
Immune checkpoint inhibitors (ICIs) have had limited success in prostate cancer when used without careful attention to sequencing and tumor microenvironment modulation. Recent preclinical data suggest that heterogeneous radiation dose patterns enhance adaptive immune priming within the tumor microenvironment and that these effects could be augmented with the addition of ICI therapy. ADT has also been shown to increase T-cell levels and immunogenic responses, potentially boosting the efficacy of immunotherapy. Investigators designed this trial to capitalize on the immunostimulatory window created by ablative-dose high-dose rate brachytherapy (HDRBT) and ADT, with nivolumab sequenced to ensure immune priming before the first brachytherapy fraction.
How was the phase 2 trial designed?
The non-randomized, single-arm, investigator-initiated phase 2 trial enrolled adult patients with localized or oligometastatic GG5 prostate adenocarcinoma between November 16, 2018, and May 26, 2021, at Moffitt Cancer Center.1,2 Eligible patients were required to have high-volume disease, defined as at least 30% positive biopsy cores with at least 12 cores sampled, to be candidates for HDRBT and at least short-term ADT, have an ECOG performance status of 0 or 1, and adequate hematologic, renal, and hepatic function. Oligometastatic disease was defined as no more than 3 distant metastatic sites and/or positive pelvic lymph nodes.
All patients received nivolumab at 240 mg every 2 weeks for 4 doses, HDRBT via two 1150-cGy implants delivered 2 weeks apart, and EBRT at 45 Gy in 25 fractions.1 Nivolumab was initiated 4 weeks prior to the first HDRBT fraction to enable immune priming. A Decipher Prostate Cancer Genomic Classifier was performed on all enrolled patients for correlative biomarker analysis.
The primary end point was the 2-year FFBR rate, with a prespecified historical control benchmark of 75%. Secondary end points included grade 3 or higher acute and late toxicity. Exploratory end points included major pathological response assessed by serial transperineal biopsies and evaluation of immune gene signatures as potential predictive biomarkers.
At baseline, the median age was 65.0 years (IQR, 57.0-69.0) and the median pretreatment PSA was 9.7 ng/mL (IQR, 7.4-18.9). The median follow-up was 38.8 months (IQR, 31.0-46.5). Most patients had an ECOG performance status of 0 (93.5%), 74.2% had stage IIIC disease, and 3 patients (9.7%) had oligometastatic disease.
What were the additional efficacy and safety data reported?
A total of 6 patients (19.3%) met criteria for biochemical recurrence during follow-up, with 3 occurring within and 3 beyond the 2-year primary end point window. All 6 patients with biochemical recurrence also developed distant metastatic disease, yielding an overall metastasis rate of 19.3%. No patients experienced a local recurrence at any time point.
Sixteen patients (51.6%) were classified as early pathological responders and 15 (48.4%) as late responders, based on serial biopsy-assessed tumor clearance. Late responders experienced more rapid progression to distant metastasis, and all late responders with treatment failure developed multisite metastases (both bone and lymph nodes), whereas early responders with treatment failure had only a single site of metastasis.
A high Ricketts Immunosuppression Score (RIS) was significantly associated with early pathological response (area under the concentration curve [AUC], 0.80; 95% CI, 0.64-0.96; P < .010) and complete radiographic response (AUC, 0.78; 95% CI, 0.61-0.96; P < .01). On multivariable analysis, low RIS was an independent predictor of metastatic disease progression (HR, 9.256; 95% CI, 1.061-80.719; P = .044), controlling for response group, ADT length, stage, and Gleason score.
In terms of safety, definitive and probable nivolumab-related toxicity included grade 2 acute adverse effects (AEs) in 6.3% of patients and grade 3 acute AEs in 6.3%, including 2 patients with grade 3 dose-limiting toxicities of autoimmune hepatitis and cardiac QT prolongation.
No grade 4 or higher nivolumab-related AEs were observed, and no late toxicities related to nivolumab were reported at any time point. Across all treatment-related events, 53.1% of patients experienced grade 2 acute toxicity and 18.8% experienced grade 3 acute toxicity. Late effects were less common, and no grade 3 or higher late AEs were observed.
"Our findings support further investigation in a larger randomized phase 2/3 study appropriately powered to compare SOC trimodality therapy with and without nivolumab in GG5 prostate cancer," Yamoah and colleagues wrote in their conclusion.
References
- Bryant JM, Sandoval M, Putney R, et al. Phase II trial of combination radiation, hormone, and immunotherapy in grade group 5 prostate cancer. J Immunother Cancer. 2026;14:e013906. doi:10.1136/jitc-2025-013906
- Combination of nivolumab immunotherapy with radiation therapy and androgen deprivation therapy. ClincalTrials.gov. Updated April 1, 2026. Accessed May 8, 2026. http://clinicaltrials.gov/study/NCT03543189
