Continuing an ARPI with [177Lu]Lu-PSMA-617 may not provide additional benefit in mCRPC

Among patients with androgen receptor pathway inhibitor (ARPI)-refractory metastatic castration-resistant prostate cancer (mCRPC), continuation of an ARPI with [177Lu]Lu-PSMA-617 (lutetium Lu 177 vipivotide tetraxetan;Pluvicto) did not improve response rates nor overall survival (OS) compared with [177Lu]Lu-PSMA-617 alone, according to data published in European Urology Oncology.¹

The real-world analysis draws on results from the VISION trial, which demonstrated the safety of combining [177Lu]Lu-PSMA-617 with ARPIs.

“Our real-world analysis suggests that continuing the ARPI alongside [177Lu]Lu-PSMA-617 may not provide additional oncologic benefits for a VISION-like patient population, who have already progressed on an ARPI and other lines of systemic therapy,” said Miguel Muniz, MD, and Daniel S. Childs, MD, lead and senior authors of the paper, respectively, in correspondence with Urology Times®. “We observed no improvement in the [prostate-specific antigen] PSA response rate nor overall survival after accounting for imbalances in baseline cohort characteristics.”

For the study, the investigators collected data on 256 patients with mCRPC from the Mayo Clinic Rochester radiopharmaceutical database. Among all patients identified, 106 (41.4%) received an ARPI alongside [177Lu]Lu-PSMA-617. According to the authors, “Those receiving an ARPI had lower baseline PSA levels (3.4 vs 29.7 ng/ml; P < .001) and lower rates of bone (77.4% vs 87.4%; P = .035) and visceral (18.9% vs 34%; P = .008) metastases.”

Key outcomes of interest included the percentage of patients achieving a PSA response of 50% or greater (PSA50), the number of treatment cycles, and OS.

Overall, data showed that patients who received an ARPI were more likely to complete all scheduled treatment cycles, with 63.2% of patients in the ARPI arm completing all 6 cycles of [177Lu]Lu-PSMA-617 vs 48.7% of patients in the [177Lu]Lu-PSMA-617 monotherapy arm (P < .001).

However, the addition of the ARPI did not appear to improve oncologic efficacy, with a similar PSA50 response rate across both arms. In total, 49.1% of patients in the ARPI arm achieved a PSA50 response vs 47.3% in the monotherapy arm (P = .786).

On univariate assessment, OS was extended with continuation of an ARPI, with the median OS not reached in the ARPI arm vs 15.3 months in the [177Lu]Lu-PSMA-617 monotherapy arm (P < .001). However, this difference was not found to be significant on multivariate analysis after adjusting for baseline differences in other prognostic variables (HR, 1.03; 95% CI, 0.68 to 1.55; P = .891), the authors reported.

Based on these data, the authors suggest that continuation of an ARPI alongside [177Lu]Lu-PSMA-617 does not appear to provide any added oncologic benefit in APRI-refractory patients. However, they note several limitations of the current analysis, including its single-center, retrospective design as well as the lack of standardized radiographic response assessment. They expressed the need for a larger trial to confirm these findings.

To that point, Muniz and Childs added, “An ongoing, open-label phase II clinical trial (NCT05849298) is investigating whether combining [177Lu]Lu-PSMA-617 with an ARPI improves outcomes in a less heavily pre-treated patient population.”

The prospective randomized trial, called PSMACare, is expected to enroll 120 patients with PSMA-positive mCRPC across 50 global clinical trial sites.² Primary completion of the study is expected in April 2028.

REFERENCES

1. Muniz M, Sartor O, Orme JJ, et al. Outcomes for [177Lu]Lu-PSMA-617 with and Without concurrent use of androgen receptor pathway inhibitors in patients with metastatic castration-resistant prostate cancer. Eur Urol Oncol. 2025:S2588-9311(25)00175-0. doi:10.1016/j.euo.2025.06.004

2. A phase II study of AAA617 alone and AAA617 in combination with ARPI in patients with PSMA PET scan positive CRPC (PSMACare). ClinicalTrials.gov. Last updated August 14, 2025. Accessed August 20, 2025. https://clinicaltrials.gov/study/NCT05849298