Lu-PSMA-617/Pembrolizumab Shows Early Efficacy in Metastatic CRPC

Multicycle [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto) plus pembrolizumab (Keytruda) displayed early efficacy and a manageable safety profile as a treatment for patients with metastatic castration-resistant prostate cancer (CRPC), according to findings from the phase 1b/2 PRINCE trial (NCT03658447) published in The Lancet Oncology.¹

Data from the efficacy analysis showed that among 37 patients treated in the single-arm study, 76% (95% CI, 59%-88%) had achieved a prostate-specific antigen (PSA) response of at least 50%. Moreover, 46% (95% CI, 29%-63%) experienced a PSA decline of at least 90%. In 10 patients with RECIST-evaluable tumors, 7 experienced a partial response (PR; 70%; 95% CI, 35%-93%).

The median PSA progression-free survival (PFS) was 8.2 months (95% CI, 5.1-11.2) in this group, and the median radiographic PFS was 11.2 months (95% CI, 5.1-14.1). In addition, the median overall survival (OS) was 20.8 months (95% CI, 13.5-not estimable [NE]). The 12- and 24-month radiographic PFS rates were 40% (95% CI, 25%-56%) and 16% (95% CI, 5%-31%), respectively, with 12- and 24-month OS rates of 84% (95% CI, 67%-92%) and 49% (95% CI, 32%-63%).

Of the 21 deaths observed on the study, 86% were attributable to disease progression. The remaining 3 were related to other causes, including subdural hematoma, fall, and respiratory arrest.

“[T]he PRINCE trial findings were broadly consistent with previous studies of [¹⁷⁷Lu]Lu-PSMA-617 treatment, suggesting that [radioligand therapy] remains the principal driver of response, with the [immune checkpoint inhibitor] component potentially conferring added benefit in a subset of biologically susceptible [tumors],” Shahneen Sandhu, MBBS, FRACP, consultant medical oncologist specializing in Uro-Oncology at the Peter MacCallum Cancer Centre, wrote in the publication with study coinvestigators.¹ “Considering the cost and potential toxicity of [immune checkpoint inhibitors], the use of biomarkers is critically important to identify the subset of [patients] most likely to benefit from combined [radioligand and immune checkpoint inhibitor] therapies.”

The single-arm study enrolled patients 18 years and older with prostate adenocarcinoma who experienced disease progression following 1 or more androgen receptor pathway inhibitors. Patients were permitted to have received prior docetaxel and must have had a life expectancy of at least 24 weeks.

[¹⁷⁷Lu]Lu-PSMA-617 was given for up to 6 cycles intravenously starting at 8.5 GBq and decreased by 0.5 GBq for each subsequent 6-week cycle. Patients also received intravenous pembrolizumab at 200 mg every 3 weeks for 24 months. Pembrolizumab was given within 2 to 4 days before [¹⁷⁷Lu]Lu-PSMA-617. Treatment was sustained in the absence of clinical progression, unacceptable toxicity, or trial withdrawal.

The co-primary end points of the study included adverse effects (AEs) and PSA response. Secondary end points included radiographic PFS, PSA PFS, OS, overall response rate, and change in health-related quality of life.

Treatment-related AEs (TRAEs) occurred in 95% of patients, mostly grade 1 or 2 in severity. The most common any grade TRAEs included xerostomia (78%), fatigue (46%), pruritus (27%), nausea (27%), rash (27%), and anorexia (16%). Additionally, 35% of patients experienced grade 3 TRAEs, including 30% of patients experiencing immune-related AEs. The most common grade 3 TRAEs included fatigue (5%), colitis (5%), and serum amylase increases (5%).

No grade 4 immune-related AEs or treatment-related deaths occurred on the study. A total of 14% of patients discontinued pembrolizumab due to immune-related AEs, including a case of grade 2 pneumonitis, grade 3 myasthenia gravis, grade 3 acute kidney injury, optic nerve neuritis and grade 3 oral mucositis, and grade 1 blurred vision. All patients continued [¹⁷⁷Lu]Lu-PSMA-617.

References

1. Sandhu S, Joshua AM, Emmett L, et al. [177Lu]Lu-PSMA-617 in combination with pembrolizumab for treatment of metastatic castration resistant prostate cancer (PRINCE): a single-arm, phase 1b/2 study. Lancet Oncol. 2026;27(4):470-479. doi:10.1016/S1470-2045(26)00017-3
2. PRINCE (PSMA-lutetium Radionuclide Therapy and ImmuNotherapy in Prostate CancEr) (PRINCE). ClinicalTrials.gov. Updated July 28, 2023. Accessed April 6, 2026. https://tinyurl.com/b7k3z2nt