Dose-Intense PSMA-targeted Radionuclide Therapy in Men with PSMA-unselected, Pre-treated Metastatic Castration-Resistant Prostate Cancer

A study aimed at determining whether dose-intense therapy with a prostate-specific membrane antigen (PSMA) regimen is effective in unselected patients with metastatic castrate-resistant prostate cancer (mCRPC) was presented by Scott T. Tagawa, MD, MS, Professor of Medicine and Urology at Weill Cornell Medicine, New York.1 The results of the study suggested that patients with “poor” baseline PSMA imaging can respond to this treatment, Dr Tagawa reported.

PSMA-targeted radionuclide therapy has been shown to benefit selected patients with pretreated mCRPC, but most studies selected patients on the basis of PSMA imaging, Dr Tagawa noted. Given the relatively low toxicity profile of these therapies, he and his colleagues have been looking at dose-intense regimens and higher potency radionuclide regimens as a way to minimize resistance brought about by repopulation and have demonstrated the feasibility and safety of more dose-intense courses of PSMA- targeted radionuclide therapy.2,3 In their latest study, they investigated whether pre-selection by PSMA imaging is necessary when employing this approach.

The study was based on data from two early-phase clinical trials that utilized dose-intense high activity levels of beta-emitting lutetium-177 (177Lu)-PSMA-617 (NCT03276572)4 or the alpha-emitter, actinium-255 (225Ac)-J591 (NCT03042468).5 The two trials enrolled patients with progressive mCRPC by Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria, with adequate bone marrow and organ function (including AND ≥2000/mm3 and platelets >150 × 109/L) and ECOG performance status 0-2. Patients had to have disease progression after at least one modern potent androgen receptor pathway inhibitor (such as abiraterone or enzalutamide) and chemotherapy (or to have refused or be ineligible for chemotherapy). Patients with prior exposure to beta-isotopes were excluded from the study, but patients who had received prior radium-223 (223Ra) or 177Lu-PSMA were eligible.

At baseline and follow-up, standard imaging (CT/ MRI) and 99m-Tc-methydiphosphonate bone scans were performed. Patients also underwent 68Ga-PSMA11 PET/CT at baseline, but this was not used to determine treatment eligibility. Treatment consisted of either dose-dense 177Lu-PSMA-617 (7.4-22.2 GB in a fractionated day 1, day 15 cycle) or a single dose of 225Ac-J591. Baseline PSMA imaging scores were used to evaluate PSA response, progression free survival (PFS) and overall survival (OS).

A total of 82 patients with heavily pretreated mCRPC were included in the analysis (50 from the 177Lu-PSMA-617 study and 32 from the 225Ac-J591 study). The median age of these patients was 70 years, median PSA was 164 and the majority (71%) were CALGB high-risk). The majority of patients (95%) had bony metastasis and 21% had liver and/or lung metastases.

Dr Tagawa pointed out that although no PSMA PET imaging-based selection was performed, all patients had PSMA uptake in at least 1 lesion and 61 (78.2%) had PSMA would not have met imaging criteria for treatment on some/ sub-studies, Dr Tagawa pointed out. Imaging and efficacy analysis showed univariate and multivariate associations of baseline PSMA imaging intensity with PSA response and PFS, but not OS, Dr Tagawa reported. Among the entire population, almost half (47.6%) experienced a >50% PSA decline. Stronger baseline PSMA imaging was associated lesions), after controlling for administered dose and CALGB (Halabi) prognostic nomogram score. Baseline PSMA imaging was also associated with PFS (P=0.04 for SUVmax of hottest lesions) on multivariable analysis. CALGB (Halabi) prognostic nomogram score was correlated with overall survival. (P=0.03). However, as previously demonstrated with 177Lu-radiolabeled J591, Dr Tagawa noted, a subset of patients with “poor” PSMA imaging responded to PSMA-targeted radionuclide therapy with 225Ac-J591.

In terms of adverse events, higher PSMA expression on baseline imaging was associated with a myeloprotective effect against pain flare (OR 0.97, P=0.004) but no other adverse events. Patients who received 177Lu-PSMA reported higher rates of xerostomia (P=0.02) compared with patients who received 225Ac-J591 patients, but the latter group reported more fatigue (P=0.001).

The results of this study support Dr Tagawa and his colleagues’ view that baseline PSMA PET patient selection prior to PSMA radionuclide therapy is helpful in optimizing drug development and response for a population receiving single-agent PSMA -targeted radionuclide therapy (for PSA response and PFS). Clinical variables (CALGB-Halabi nomogram) appear to be more prognostic than baseline PET for OS. A small percentage of patients with “poor” baseline PSMA imaging might benefit from PSMA-targeted radionuclide therapy, particularly antibody-delivered 225Ac- J591, Dr Tagawa concluded.


  1. Tagawa ST, Sun M, Thomas C, et al . PSMA imaging and outcome following dose-intense PSMA-targeted radionuclide therapy in men with PSMA-unselected, pre-treated, metastatic castration-resistant prostate cancer. Poster #97 presented at the 22nd Annual Meeting of the Society of Urologic Oncology (SUO), December 1-3, 2021, Orlando, FL.
  2. Rasul S, Hacker M, Kretschmer-Chott E, et al. Clinical outcome of standardized 177Lu- PSMA-617 therapy in metastatic prostate cancer patients receiving 7400 MBq every 4 weeks. Eur J Nucl Med Mol Imaging. 2020;47(3):713-720. DOI: 10.1007/s00259-019- 04584-1
  3. Rathke H, Giesel FL, Flechsig P, et al. Repeated 177Lu-labeled PSMA-617 radioligand therapy using treatment activities of up to 9.3 GBq. J Nucl Med. 2018;59(3):459-465. DOI: 10.2967/jnumed.117.194209
  4. Tagawa ST, Sun M, Sartor O, er al. Final results of phase I/II trial of fractionated dose 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2021;32(S5):s645. Abstract 600. DOI: 10.1016/j.annonc.2021.08.1113
  5. Tagawa ST, Sun M, Sartor O, et al. Phase I study of 225Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2021; 39(15 suppl):Abstract 5015. DOI: 10.1200/JCO.2021.39.15_suppl.5015