The phase 2 EVOLUTION trial suggests that adding dual immune checkpoint blockade to radioligand therapy may modestly improve disease control in patients with advanced metastatic castration-resistant prostate cancer (mCRPC), a setting historically resistant to immunotherapy.
Key Efficacy Signals
When compared with lutetium-177-PSMA alone, the addition of nivolumab plus ipilimumab was associated with numerically superior disease-control metrics.
PSA-based progression-free survival showed a modest median improvement (7.6 vs 7.1 months), but a more notable difference emerged at longer follow-up, with 12-month PSA-PFS rates of 33% versus 17%. A similar pattern was observed radiographically: median rPFS was 12.0 months with the combination compared with 8.5 months for radioligand therapy alone, and 12-month rPFS rates were 47% versus 23%, respectively.
While the absolute median gains were limited, the widening separation of the survival curves over time suggests that a subset of patients may achieve more durable benefit when immunotherapy is layered onto Lu-177–PSMA, supporting further exploration of patient selection strategies.
Response Signals
- PSA ≥50% decline: 75% vs 67%
- PSA ≥90% decline: 46% vs 43%
- Objective response rate (RECIST v1.1): 71% vs 50%
- Radioligand discontinuation for deep response: 16% in the combination arm
These findings raise the possibility that immune modulation may enhance depth of response to targeted radioligand therapy in selected patients.
Study Population and Trial Design
The study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) who had previously received at least one androgen receptor pathway inhibitor (ARPI) and had a preserved functional status (ECOG 0–1). Eligibility required high PSMA expression, defined by a SUVmax ≥15 at the dominant disease site, ensuring selection of patients most likely to benefit from PSMA-targeted radioligand therapy.
Participants were randomized in a 2:1 ratio to receive either lutetium-177-PSMA alone (n=33) or lutetium-177-PSMAin combination with dual immune checkpoint blockade (n=67). The immunotherapy strategy followed an induction–maintenance paradigm, with combination induction using nivolumab and ipilimumab, followed by nivolumab maintenance for up to 24 months.
This design was intended to test whether immune priming and sustained checkpoint inhibition could enhance and prolong the antitumor effects of PSMA-directed radioligand therapy in a biologically selected mCRPC population.
Safety Profile
The safety findings were largely in line with the established toxicity profiles of PSMA-targeted radioligand therapy and immune checkpoint blockade. The most frequently reported adverse events included fatigue, xerostomia, nausea, rash, and diarrhea, reflecting overlapping effects of lutetium-177-PSMA and immune activation from checkpoint inhibition.
Notably, treatment discontinuation of immunotherapy was common, with 58% of patients stopping therapy due to adverse events. This high discontinuation rate underscores the tolerability challenges associated with dual checkpoint blockade—particularly the combination of nivolumab and ipilimumab—in the mCRPC setting. These findings highlight the need for careful patient selection, toxicity mitigation strategies, and potentially alternative dosing or sequencing approaches when integrating immunotherapy with radioligand treatments in prostate cancer.
Clinical Interpretation
The EVOLUTION trial provides proof-of-concept that combining radioligand therapy with immune checkpoint inhibition can modestly extend disease control in mCRPC. However, the benefit appears incremental rather than transformative, and toxicity remains a key limitation.
The data reinforce two broader themes in prostate cancer immunotherapy:
- Radiation-based strategies may help “prime” immune-cold tumors
- Durable benefit likely depends on biomarker-defined patient selection
Further studies are needed to identify which patients derive meaningful long-term benefit and whether alternative immunotherapy strategies can improve efficacy without compromising tolerability.
You Can Watch More on OncoDaily Youtube TV