ESMO 2025: Optimized Use of Radioligand Therapy in mCRPC

(UroToday.com) The 2025 ESMO annual meeting featured a metastatic castration-resistant prostate cancer (mCRPC) session and a presentation by Dr. Irene Burger discussing optimized use of radioligand therapy in mCRPC. Dr. Burger started her presentation by emphasizing that there are many ways to improve outcomes in mCRPC with radioligand therapy (both ¹⁷⁷Lu-PSMA-617 and radium-223), but the ultimate aim is to improve outcomes and quality of life. For her presentation, Dr. Burger focused on five ways to optimize use of radioligand therapy.

First, improving patient selection for radioligand therapy based on PSMA PET/CT. The phase 3 VISION trial evaluated ¹⁷⁷Lu-PSMA-617 in men with PSMA-positive mCRPC who had previously received treatment with a next-generation androgen receptor signaling inhibition (abiraterone, enzalutamide, etc) and one or two prior lines of taxane chemotherapy:

There were two alternate primary endpoints: radiographic progression free survival and overall survival. Treatment with ¹⁷⁷Lu-PSMA-617 + standard of care significantly improved radiographic progression free survival, treatment with ¹⁷⁷Lu-PSMA-617 + standard of care significantly improved radiographic progression free survival by a median 5.3 months (median radiographic progression free survival, 8.7 versus 3.4 months; HR 0.40, 99.2% CI 0.29 to 0.57; p < 0.001, one-sided). For overall survival ¹⁷⁷Lu-PSMA-617 improved overall survival by a median of 4.0 months (median overall survival: 15.3 versus 11.3 months; HR 0.62, 95% CI 0.52 to 0.74; p < 0.001, one-sided), compared to standard of care alone:

To explore the association between quantitative baseline ⁶⁸Ga-PSMA-11 PET/CT parameters and treatment response and outcomes in the VISION trial, Kuo et al. found that whole-body tumor SUV_mean was the best predictor of ¹⁷⁷Lu-PSMA-617 efficacy, with a HR range of 0.86-1.43 for all outcomes (all p < .001).² A 1-unit whole-body tumor SUV_mean increase was associated with a 12% and 10% decrease in risk of a radiographic progression free survival event and death, respectively. Presented at ESMO 2025 by Herrmann et al., patients in the ¹⁷⁷Lu-PSMA-617 arm of PSMAfore with an SUV_mean ≥ median had longer radiographic progression free survival than those with SUV_mean < median:

Thus, Dr. Berger emphasized that patients with SUV_mean > 9-10 have more benefit from ¹⁷⁷Lu-PSMA-617 radioligand therapy. Additionally, patients with PSMA PET and PDG PET mismatch lesions also have improved benefit from ¹⁷⁷Lu-PSMA-617 radioligand therapy:

Second, scheduling and the number of radioligand therapy cycles given. In PSMAfore,³ 7.4 GBq of ¹⁷⁷Lu-PSMA-617 every 6 weeks was given for up to 6 cycles (up 44.4 total GBq), with a median radiographic progression free survival of 12.0 months. On the contrary, in SPLASH (presented at ESMO 2024), 6.8 GBq of ¹⁷⁷Lu-PNT2000 every 8 weeks was given for up to 4 cycles (up to 27.2 total GBq), with a median radiographic progression free survival of 9.5 months:

Currently, Dr. Berger endorses 6 x 7.4 GBq every 6 weeks rather than 4 x 6.8 GBq every 8 weeks based on the more impressive radiographic progression free survival in PSMAfore.

Third, therapy monitoring for PSMA radioligand therapy. Prostate cancer changes over the course of the disease process and treatments received. After progression on ADT, there is a decrease in androgen receptor expression and increase in PSMA expression, and after radioligand therapy, partial responders have a decrease in PSA and PSMA tumor volume. However, in progressive disease after radioligand therapy, there may be (i) increased PSA and increased PSMA tumor volume, or (ii) decreased PSA and decreased tumor volume. Thus, it is important to consider not just PSMA PET/CT in follow-up, but also ¹⁸F-FDG PET in situations where there may be PSA and clinical discordance, as highlighted in the following patient example:

PSMA PET/SPECT is good for monitoring, as long as it is in line with the clinical picture and laboratory results. Dr. Berger cautions that we must be aware of potential negative selection of PSMA negative tumors after radioligand therapy, and consider alternative imaging if progression is suspected (FDG PET, DWI MRI, etc).

Fourth, assessing the ideal time point for PSMA radioligand therapy. In addition to VISION, SPLASH, and PSMAfore in the mCRPC space, we have seen at ESMO 2025 presentations on LUNAR for ¹⁷⁷Lu-PSMA in the oligometastatic mHSPC setting, as well as PSMAddition for ¹⁷⁷Lu-PSMA in mHSPC, and previously LuTectomy⁴ with ¹⁷⁷Lu-PSMA for patients with high risk localized disease. In the mCRPC setting, is the ideal time point before or after a taxane? In addition to the previously published PSMAfore trial in the pre-chemotherapy mCRPC space, data from the Canadian Cancer Trials Group (CCTG) PR21 trial (presented at ESMO 2025) randomized mCRPC patients to docetaxel versus ¹⁷⁷Lu-PSMA-617. Patients receiving ¹⁷⁷Lu-PSMA-617 had a median radiographic progression free survival of 8.6 months versus 10.7 months for docetaxel (HR 1.01, 90% CI 0.77-1.31):

Screenshot_2025-10-20_at_9.12.26 PM.png

With regards to overall survival, the median was 14.3 months for ¹⁷⁷Lu-PSMA-617 to docetaxel versus 18.2 months for docetaxel to ¹⁷⁷Lu-PSMA-617 (HR 1.64, 95% CI 1.14, 2.35), suggesting a benefit for earlier use of docetaxel and later use of ¹⁷⁷Lu-PSMA-617:

Screenshot_2025-10-20_at_9.12.37 PM.png

In LUNAR, also presented at ESMO 2025, patients with 1–5 PSMA PET–positive lesions were randomized 1:1 to receive either stereotactic body radiotherapy alone or two cycles of ¹⁷⁷Lu-PNT2002 (6.8 GBq every 8 weeks) followed by stereotactic body radiotherapy. After a median follow-up of 22 months (IQR 19–26), the LUNAR trial met its primary endpoint of progression free survival. The addition of radioligand therapy significantly prolonged median stereotactic body radiotherapy to 17.6 months (95% CI 15 to not reached) compared to 7.4 months (95% CI 6.0–13.5) with stereotactic body radiotherapy alone (HR 0.37, 95% CI 0.22–0.61, p<0.0001):

Screenshot_2025-10-20_at_9.12.50 PM.png

In PSMAddition (also presented at ESMO 2025), men with untreated or minimally treated mHSPC and ≥1 PSMA-positive metastatic lesion on ⁶⁸Ga-PSMA-11 PET/CT were randomized to:

Experimental arm: ¹⁷⁷Lu-PSMA 617 (7.4 GBq ±10% 6 cycles every 6 weeks) + ADT + androgen receptor pathway inhibitor
Control arm: ADT + androgen receptor pathway inhibitor
- Crossover to the ¹⁷⁷Lu-PSMA 617 arm was permitted upon radiographic progression

The study met its primary endpoint with radiographic progression free survival significantly prolonged with the addition of ¹⁷⁷Lu-PSMA-617 (HR 0.72, 95% CI 0.58-0.90, p = 0.002). Median radiographic progression free survival has not been reached in either arm yet:

However, the adverse event profile was not insignificant for a cumulative dose of 44.4 GBq of ¹⁷⁷Lu-PSMA-617 in the mHSPC setting:

Dry mouth: 46% versus 4%
Nausea: 34% versus 9%
Constipation: 18% versus 16%
Decreased appetite: 14% versus 6.5%
Vomiting: 14% versus 4%

Fifth, assessing safety and efficacy of different radionuclides such as ²²⁵Actinium and ¹⁶¹Terbium. ²²⁵Ac-PSMA-617 radioligand therapy has shown preliminary evidence of clinical efficacy in patients with mCRPC⁵ and may represent a viable treatment option in patients who have received previous lines of therapy:

²²⁵Ac-PSMA-617 was assessed in the retrospective multicenter study WARMTH Act, specifically 488 patients at 7 centers. ²²⁵Ac-PSMA-617was associated with a median overall survival of 15.5 months and median progression free survival of 7.9 months. Any PSA decline was noted in 73% of patients and PSA50 response was noted in 57% of patients.

¹⁶¹Tb-PSMA-I&T was assessed in the VIOLET single center, single arm phase 1/2 study.⁶ Among 30 eligible patients, 20 (67%) of 30 patients had received previous docetaxel. There were no dose-limiting toxicities and the maximum administered dose and recommended phase 2 dose was 7.4 GBq. Grade 3 treatment related adverse events were limited to pain (1, 3%; the only serious treatment related adverse events) and lymphopenia (1, 3%). No grade 4 treatment related adverse events or treatment-related deaths occurred. The PSA50 response rate for ¹⁶¹Tb-PSMA-I&T was 70% (95% CI 51-85) and the PSA90 response rate was 40% (95% CI 23-59):

An example of 3-time point quantitative SPECT @ cycle 1 is highlighted in the following figure:

Dr. Burger also noted that improved biodistribution is necessary, specifically tuning the strength of the albumin binding group altering tumor uptake and the therapeutic index:

Dr. Burger concluded this presentation discussing optimized use of radioligand therapy in mCRPC with the following take home points:

Patient selection based on PSMA PET:
- Patients with SUV_mean > 9–10 benefit more from radioligand therapy
- Patients without mismatch lesions also derive greater benefit
Numbers of cycles and scheduling:
- 6×7.4 GBq every 6 weeks is > 4×6.8 GBq every 8 weeks
- More than 6 cycles seems safe and effective
- Shorter intervals for aggressive disease might be better
Therapy monitoring:
- Cave: for PSMA negative tumors after radioligand therapy
- Consider ceCT / FDG / DWI if progression is suspected
Ideal time point of radioligand therapy:
- Still an open question and depends on the radionuclide
Different radionuclides / improved biodistribution:
- ¹⁶¹Tb and ²²⁵Ac – have the potential to bring more efficacy, however the side-effect profile needs consideration
- Tailoring albumin binding might improve the side effect profile and efficacy
Combinations with radioligand therapy
Different targets

Presented by: Irene A. Burger, UniversitatsSpital Zurich, Zurich, Switzerland

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 European Society for Medical Oncology (ESMO) Annual Congress, Berlin, Germany, October 17–21, 2025

References:

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