ASCO 2020: TheraP: A Randomised Phase II Trial of 177Lu-PSMA-617 Theranostic Versus Cabazitaxel in Metastatic Castration Resistant Prostate Cancer Progressing after Docetaxel: Initial Results (ANZUP protocol 1603)

( PSMA therapies target the prostate-specific membrane antigen, a cell surface protein found on prostate cancer, and some normal prostate tissue.1  Multiple radioisotopes are being developed to link with PSMA, including lutetium-177 (177-Lu), a beta particle emitter. In a prior single-center single-arm study of Lutetium-177 [177Lu]-PSMA-617 in patients who had heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) after second-generation anti-androgen therapy and taxane chemotherapy, 17 (57%) of 30 patients achieved a PSA decline of 50% or more.2 This is the first randomized study that evaluates 177Lu-PSMA-617 vs cabazitaxel for men with mCRPC after docetaxel.


200 men were randomized to either LuPSMA or cabazitaxel. To screen into the study, all men had both 68Ga-PSMA-11 and 18F-FDG PET/CT and were required to have high PSMA-expression and no sites of FDG-positive/PSMA-negative disease. Other inclusion criteria are shown above. Of note, these were robust patients who had already completed docetaxel and were eligible for cabazitaxel, all with a PSA>20. Baseline characteristics are shown below:


The majority of patients had either enzalutamide or abiraterone and had widespread disease, most over 20 sites of disease.

Patients randomized to LuPSMA received 6-8GBq every 6 weeks for up to 6 cycles of therapy and patients randomized to cabazitaxel received 20 mg/m2 every 3 weeks for up to 10 cycles. Patients were stratified based on disease burden and prior anti-androgen therapy. 


Of note, about 1/3 of patients who had registered for the study (91/291) were ineligible prior to randomization, either because of low PSMA expression or FDG discordant disease. An example of both PSMA negative and PSMA discordant disease are shown in the bottom left. The patient second from the left has liver metastases on the FDG PET but no disease on PSMA and thus was excluded.


After a median follow up of 13 months, LuPSMA significantly improved PSA-PFS compared with cabazitaxel (HR 0.69) and had a much higher PSA50 rate (66% vs 37%) compared with cabazitaxel. 


The primary endpoint of this study was PSA50 and secondary endpoints included PSA PFS and overall survival.  An early look at the PFS endpoint based on 157 of the required 170 events shows a hazard ratio of 0.69 at this time but is has not been finalized.

In terms of safety, Cabazitaxel had more neutropenia, diarrhea, dysgeusia, and neuropathy compared with Lu-PSMA. Lu-PSMA had more thrombocytopenia, dry mouth, and dry eyes. 54% of men had grade 3/4 toxicity with cabazitaxel compared to 35% of men with Lu-PSMA. Most patients completed both therapies – only 1 discontinued in Lu-PSMA and 3 with cabazitaxel.


For men with mCRPC after docetaxel and anti-androgen therapy, LuPSMA demonstrated a greater PSA50 response over cabazitaxel with a toxicity profile. As demonstrated in the screening process in this trial, not all patients will qualify for LuPSMA, due to low or discordant PSMA activity compared with FDG PET. However, for patients who do, the majority of patients will see a PSA response. PFS data is immature at this time but looks favorable thus far. Overall survival data pending, both from this study and VISION, a large phase III study which randomizes patients to either 177Lu-PSMA-617 plus best supportive care or best standard of care only. We eagerly away OS data, as this new class of therapeutics may provide additional benefit for men with heavily pre-treated mCRPC.

Presented by: Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, FICIS, Nuclear Medicine and Molecular Imaging physician, Peter MacCallum Cancer Centre, Melbourne, Australia, 

Written by: Jason Zhu, MD. Medical Oncologist, Division of Genitourinary Cancers, Levine Cancer Institute, Twitter: @TheRealJasonZhu, at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.


  1. Chang SS. Overview of prostate-specific membrane antigen. Reviews in urology 2004;6:S13.
  2. Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. The Lancet Oncology 2018;19:825-33.
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