(UroToday.com) The 2025 PSMA and Beyond annual meeting featured a LuPSMA therapy session and a presentation by Dr. Jeremie Calais discussing clinical trials of PSMA radioligand therapy in 2025. Dr. Calais noted that his sources for identifying trials including clinicaltrials.gov (searched March 26, 2025), ASCO 2024 trials in progress, ESMO 2024 trials in progress, ASCO GU 2025 trials in progress, and UroToday, which led to selection of 70 trials. Beyond VISION,1 PSMA radioligand therapy is moving into earlier and later indications:
In the pre-chemotherapy mCRPC setting, phase 3 Lu-177 PSMA trials include PSMAfore, SPLASH, ECLIPSE, and ProstACT GLOBAL†.
† ProstACT GLOBAL evaluates antibody-based Lu-177-TLX591; patients are post-ARPI and taxane-naïve at entry
Both PSMAfore and SPLASH demonstrated a radiographic progression free survival benefit in the LuPSMA intervention arm compared to the androgen receptor pathway inhibitor switch control arm:
For Lutetium-177 PSMA versus chemotherapy, there are three phase 2 randomized clinical trials: TheraP,3 PLUDO CCTG PR21, and CATCH-177:
PLUDO CCTG PR21 is randomizing 200 mCRPC men pre-chemotherapy to Lu-177 PSMA-617 versus docetaxel with the following trial design:
Currently there are three phase 3 randomized trials assessing Lutetium-177 in the mHSPC disease space: PSMAddition, PEACE-6 for poor responders, and STAMPEDE-2:
PSMAddition completed recruitment in 2023 with an estimated study completion date of February 2026. The trial design for PSMAddition is as follows:
STAMPEDE-2 is a phase III, randomized, open label, multi-center platform protocol testing treatments in patients with metastatic prostate cancer starting ADT. The platform will include 8,000 total patients, is funded by AAA/Novartis, is sponsored by University College London, and coordinated by the MRC CTU at University College London. The trial design of STAMPEDE-2 is highlighted below:
Moving to Lutetium-177 PSMA for oligometastatic hormone sensitive prostate cancer, there are seven phase 2 randomized trials of PSMA radioligand therapy + stereotactic ablative radiotherapy versus stereotactic ablative radiotherapy alone. These include a City of Hope trial, RAVENS, BULLSEYE, LUNAR, ProstACT TARGET, POPSTAR II, and PSMA-DC:
The LUNAR trial (NCT05496959) is randomizing men with oligorecurrent prostate cancer naïve to ADT within the last 6 months or hormone sensitive and 1-5 sites of disease outside the prostate or prostate bed on PSMA PET/CT to two cycles of 177Lu-PNT2002 versus stereotactic body radiotherapy to all sites of PSMA PET/CT defined disease. The primary endpoint of progression free survival is expected to read out later this year.
The high risk localized prostate cancer disease space is also busy with Lutetium-177 PSMA trials, including seven clinical trials of neoadjuvant or adjuvant PSMA radioligand therapy. These include Lutectomy,4 NEPI, LUPUS, STARLiT, PRELUDE, PSMA-ADJUVO, and NeoPSMA:
The LUPUS trial is a phase 1-2 single arm trial of 20 patients treated with neoadjuvant intra-arterial Lu-177-PSMA-617:
With regards to long term safety of Lu-177-PSMA-617, there is a phase 4 trial assessing long term follow-up of Lu-177-PSMA-617 patients, with CTCAE monitoring every 6 months for 10 years, which was initiated in 2023.
Currently, there are 9 trials addressing dosing modulation of Lutetium-177 PSMA, which include: Dose-Escalation LuPSMA, RESIST-PC, FLEX-MRT, RadioDose, MI-BET De-escalation, Re-LuPSMA, ReaLuP, PRODIGY-1, and LPS-boost:
Dr. Calais then discussed Actinium-225 PSMA therapy trials, for which there 11 trials: single dose escalation, fractionated multiple dose, AcTIOn, TATCIST, SatisfACtion, FL-020, ACCEL, CONVERGE-01, AlphaBreak, NeoPSMA, and PSMAcTION:
For novel radionuclides, there are three prospective trials of PSMA radioligand therapy, including SECuRE, VIOLET, and TheraPb all in mCRPC. SECuRE is assessing two doses of Cu-67-SAR-bisPSMA, VIOLET is assessing 6 x 6 week doses of Tb-161-PSMA-I&T, and TheraPb is assessing dose escalation to 4-6 cycles of Pb-212-ADVC001:
There are also 6 trials ongoing assessing PSMA radio-antibody J591, which include: single dose escalation Ac225 J591, fractionated multiple dose 225Ac J591, ProstACT Select, ProstACT TARGET, CONVERGE-01, and ProstACT Global:
What about after Lutetium-177 PSMA therapy? Dr. Calais highlighted that there are 7 prospective trials for post-LuPSMA patients: AcTIOn, TheraPb, PRO-XL, AlphaBreak, RE-LuPSMA, REALuP, PSMAcTION:
Recently, there has been increasing interest in trials assessing a combination of PSMA radioligand therapy and androgen receptor pathway inhibitors. Dr. Calais notes 6 trials assessing this combination therapy, including PEACE-3, ARROW, ENZA-p,5,6 PSMACare, PSMAndARPI, and AcTFirst:
Briefly, ENZA-p recently showed a survival benefit6 for the combination of enzalutamide + Lu-177-PSMA-617 versus enzalutamide monotherapy (HR 0.55, 95% CI 0.36-0.84):
Similarly, there are 5 prospective trials assessing the combination of PSMA radioligand therapy and chemotherapy, including J591 + docetaxel, DORA, UpFrontPSMA,7 LuCAB, and LuCarbo:
Results of the UpFrontPSMA trial were presented at ESMO 2024 and subsequently published in Lancet Oncology. This trial included patients with de novo high-volume mHSPC who had received ≤4 weeks of ADT and had a PSA >10 ng/ml at diagnosis. Prior to randomization patients underwent both PSMA and FDG PET scans. Eligibility was limited to those patients with evidence of high tumor uptake and high-volume disease on PET scans. Patients were also required to have the majority of their metastatic disease demonstrating PSMA positivity. Eligible patients were randomized to:
- Experimental arm: 177Lu-PSMA-617 7.5 GBq x 2 cycles + docetaxel 75 mg/m2 x 6 cycles
- Control arm: Docetaxel 75 mg/m2 x 6 cycles
Time-to-event analyses demonstrated that patients in the experimental arm had superior PSA progression-free survival (median: 31 versus 20 months; HR 0.60, p = 0.039) and freedom from castration resistance (HR 0.60, p = 0.033):
For the combination of PSMA radioligand therapy and immune checkpoint inhibitors, there are five trials assessing combinations: PRINCE, LuPSMA + Pembro,8 Ac-J591 + AntiPD1 + androgen receptor inhibitor, EVOLUTION, and NEPI:
In the UCSF LuPSMA + Pembro trial, a single dose of LuPSMA was followed by a maintenance dose of pembrolizumab among 43 mCRPC patients, with a median follow-up of 16.5 months (IQR 12.2-21.9). Overall, 44% of patients had a PSA50 response and 16% of patients had a PSA90 response:
There are also two prospective trials of combination PSMA radioligand therapy + DNA damage repair inhibitors: LuPARP and UPLIFT:
LuPARP was initially presented at ASCO 2023, a phase I trial of 48 patients with mCRPC. In the overall cohort (i.e., Cohorts 1 to 9), the PSA50 and PSA90 response rates were 66% and 44%, respectively, and the objective response rate by RECIST v1.1 criteria was 78%:
Dr. Calais also discussed two prospective trials of combination alpha and beta radioligand therapy, Ac-J591 + Lu-I&T and AlphaBet:
Finally, Dr. Calais discussed the NEPC study, an exploratory safety and efficacy study with PSMA, SSTR, and GRPR targeted radioligand therapy in metastatic neuroendocrine prostate cancer. This is a phase 1 multicenter study of 36 patients whereby radioligand therapy targeting PSMA, SSTR2, or GRPR will be given every 6 weeks as an IV injection. Neuroendocrine prostate cancer will be defined as:
- Small cell or neuroendocrine by histopathology, or
- Chromogranin synaptophysin by immunohistochemistry, or
- M1c disease progression without PSA progression, or
- Chrom A > 5N/Neuron-specific enolase > 2N, or
- PTEN/Tp53/RB loss
Presented by: Jeremie Calais, MD, PhD, University of California, Los Angeles, Los Angeles, CA
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 PSMA and Beyond Annual Meeting, Los Angeles, CA, Fri, Mar 28 – Sat, Mar 29, 2025.
References:
- Sartor O, de Bono J, Chi KN et al. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103.
- Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naïve patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): A phase 3, randomized, controlled trial. Lancet 2024 Sep 28;404(10459):1227-1239.
- Hofman MS, Emmett L, Sandhu S, et al. [(177)Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet. 2021 Feb 27;397(10276):797-804.
- Eapen RS, Buteau JP, Jackson P, et al. Administering [177Lu]Lu-PSMA-617 Prior to Radical Prostatectomy in Men with High-risk Localized Prostate Cancer (LuTectomy): A Single-centre, single-arm, phase 1/2 study. Eur Urol. 2023 Oct 25:S0302-2838(23)03087-7.
- Emmett L, Subramaniam S, Crumbaker M, et a. [177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): An open-label, multicentre, randomized, phase 2 trial. Lancet Oncol. 2024 May;25(5):563-571.
- Emmett L, Subramaniam S, Crumbaker M, et al. Overall survival and quality of life with [177Lu]Lu-PSMA-617 plus enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer (ENZA-p): Secondary outcomes from a multicentre, open-label, randomized, phase 2 trial. Lancet Oncol. 2025 Feb 12 [online ahead of print].
- Azad AA, Bressel M, Tan H, et al. Sequential [(177)Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone sensitive prostate cancer (UpFrontPSMA): A multicentre, open label, randomized, phase 2 study. Lancet Oncol. 2024 Oct;25(10):1267-1276.
- Aggarwal R, Starzinski S, de Kouchkovsky I, et al. Single-dose 177Lu-PSMA617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: An open-label, dose-expansion, phase 1 trial. Lancet Oncol. 2023 Nov;24(11):1266-1276.