APCCC 2021: Contagious Enthusiasm in PSMA-Driven Therapeutics

(UroToday.com) The Advanced Prostate Cancer Consensus Conference 2021 virtual meeting session discussing PSMA in diagnostics and therapy included a presentation by Dr. Eleni Efstathiou discussing the contagious enthusiasm of PSMA-driven therapeutics. Dr. Efstathiou notes that the VISION study outcomes1 have set the bar high, with 177Lu-PSMA-617 targeted radioligand therapy improving overall survival (OS), radiographic PFS, and quality of life by a significant margin in advance metastatic castration resistant prostate cancer (mCRPC):




Dr. Efstathiou highlighted that there are several therapeutic index improvement strategies:

  • Development in the earlier disease setting
  • Combinatorial strategy: synergy, additive effect, overcoming heterogeneity driven resistance
  • Alternative agents: improved efficacy and/or (or not) improved safety
  • Precision in patient selection and treatment allocation


 Currently, there are efforts to treat with radioligand therapy earlier in the disease spectrum. This includes the Bullseye trial (177Lu-PSMA-I&T) and ENZA-P trial (177Lu-PSMA-617 + enzalutamide) as first-line therapy for mCRPC, the PSMAddition trial (177Lu-PSMA-617) and UpFrontPSMA trial (177Lu-PSMA-617) as first-line therapy for mHSPC, and the LuTectomy trial (177Lu-PSMA-617) as neoadjuvant therapy for localized disease:




 The PRINCE phase Ib trial was initially presented at ESMO 2021, testing 177Lu-PSMA-617 targeted radioligand therapy + pembrolizumab in mCRPC men. In this trial, patients with mCRPC patients with high PSMA expression without discordant FDG avid disease on paired PSMA and FDG PET/CT scans received up to 6 cycles of Lu-PSMA-617 (6-8 GBq) every 6 weeks in conjunction with 200mg of pembrolizumab every 3 weeks for up to 2 years. With a median follow-up of 38 weeks, the PSA50 response rate was 73% (27/37 [95% CI: 56-86]):




Among the 9 patients with RECIST measurable disease, 7 (78%) had a partial response. Further, rPFS and PSA-PFS at 24 weeks were 64% (95% CI: 45-79) and 68% (95% CI: 50-81), respectively:




 Alternative radiopharmaceuticals to the beta emitting 177Lu-PSMA-617 targeted radioligand therapy include utilization of alpha particles. The rationale for utilization of alpha particles is a higher linear energy transfer, with a shorter range of effect; indeed, there is great anticipation of improved efficacy and safety with this class of therapeutics. Clinical reports are still limited/preliminary and mainly include 225Act-PSMA-617, which has shown potential activity in patients resistant to 177Lu-PSMA-617 targeted radioligand therapy [2] and in patients with CNS disease. Ongoing trials using alpha emitters include (i) a phase 1b trial assessing Actinium-225-J591 antibody (NCT03276572), and (ii) a phase 1b trial assessing Thorium-227-PSMA-TTC antibody (NCT03724747). PSMA-targeted bispecific T-cell engager (BiTE) immunotherapy has also been tested in the phase 1 setting:




Among patients receiving acapatamab, the PSA50 rate was 50%, with a 91% grade 1/2 adverse event rate for cytokine releasing syndrome [3]. PSMA-targeted CAR-T development is in the embryonal stage limited by population vulnerability, with 5 trials ongoing (2 in the USA, 2 in China, and 1 in Germany).


Dr. Efstathiou concluded her presentation by emphasizing that with regards to precision in patient selection and treatment allocation, it is important to make the most of all available resources.

Presented by: Eleni Efstathiou, MD, Department of Genitourinary Medical Oncology, Houston Methodist, Houston, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 Advanced Prostate Cancer Consensus Conference, Saturday, October 9, 2021.


  1. 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.
  2. Feuerecker B, Tauber R, Knorr K, et al. Activity and adverse events of Actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of Lutetium-177-PSMA. Eur Urol 2021 Mar;79(3):343-350.
  3. Einsele H, Borghaei H, Orlowski RZ, et al. The BiTE (bispecific T-cell engager) platform: Development and future potential of a targeted immuno-oncology therapy across tumor types. Cancer 2020;126(14):3192-3201.