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Early Phase 2 Data Promising for Lutetium-177 PSMA-617 in Metastatic Prostate Cancer

August 2020 Vol 13, Special Issue: Payers' Perspectives in Oncology - Prostate Cancer
Phoebe Starr

Early results from the phase 2 TheraP clinical trial show that the targeted radiation therapy Lutetium-177 PSMA-617 (Lu-PSMA) significantly improved prostate-specific antigen (PSA) response compared with standard cabazitaxel in men with metastatic castration-resistant prostate cancer (CRPC) that progressed after docetaxel therapy. In addition, Lu-PSMA had an improved toxicity profile compared with cabazitaxel. The results of this study were presented at the ASCO 2020 virtual annual meeting.

Lu-PSMA directly targets the prostate-specific membrane antigen (PSMA), which is expressed uniquely by prostate cancer cells. This radioligand agent binds to PSMA and delivers radiation directly to tumor sites. An early look at this phase 2 clinical trial of a promising approach was greeted with enthusiasm, and the overall survival data are eagerly awaited.

“This is the first randomized phase 2 trial to compare Lu-PSMA with a standard of care in men with docetaxel-progressing metastatic CRPC,” stated lead investigator Michael S. Hofman, MBBS, FRACP, FAANMS, FICIS, Program Director, Prostate Theranostics and Imaging Centre of Excellence, Peter MacCallum Cancer Centre, Melbourne, Australia. “Cabazitaxel, the comparator, is a relevant comparator that has been shown to improve overall survival in men who progress on docetaxel,” he added.

“In men with progressive disease following docetaxel, Lu-PSMA was more active than cabazitaxel, with relatively fewer grade 3 and 4 adverse events and PSA progression-free survival favoring Lu-PSMA in this preliminary analysis. Lu-PSMA represents a potential new class of effective therapy for men with metastatic CRPC,” Dr Hofman stated.

TheraP Clinical Trial

TheraP is the first randomized clinical trial to compare Lu-PSMA therapy and cabazitaxel in men with docetaxel-progressing metastatic CRPC, which is defined by rising PSA and PSA >20.

The investigators randomized 200 patients in a 1:1 ratio to Lu-617 for every-6-week cycles for up to 6 cycles or to cabazitaxel 20 mg/m2 every 3 weeks for up to 10 cycles. If a deep response was observed in the Lu-PSMA arm, treatment was paused and restarted at disease progression.

The patients were stratified by disease burden, previous treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga), and study site. Of 200 randomized patients, 98 received treatment with Lu-PSMA and 85 received cabazitaxel.

At baseline, the treatment arms were well-balanced. Approximately 91% of the patients had previously received enzalutamide or abiraterone acetate, 78% had a high disease burden (>20 metastatic sites), and 92% had an Eastern Cooperative Oncology Group performance status score of 0 or 1. The median PSA level was 110 ng/mL in the Lu-PSMA arm and 94 ng/mL in the cabazitaxel arm. More than 50% of patients had a Gleason score of ≥8 at diagnosis, and approximately 30% of patients had a Gleason score of ≤7.

The median follow-up was 13.3 months. For the primary end point, an intent-to-treat analysis showed that Lu-PSMA led to a significantly greater percentage of patients with a PSA decline of ≥50% (66% with Lu-PSMA vs 37% with cabazitaxel), representing a 29% absolute greater PSA response in the experimental arm compared with cabazitaxel (P <.0001). In a separate sensitivity analysis, the difference in PSA response between the 2 study arms remained significant, at 23%, favoring Lu-PSMA (P = .0016).

Early data on progression-free survival showed that Lu-PSMA delayed disease progression by 31% compared with cabazitaxel.


Febrile neutropenia was more common with cabazitaxel than with Lu-PSMA—13% versus 4%, respectively. Cabazitaxel was also associated with more diarrhea, change in taste, and neuropathy than Lu-PSMA. By contrast, more cases of thrombocytopenia, dry mouth, and dry eye were reported in patients who received treatment with Lu-PSMA.

Grade 3 or 4 adverse events were more common with cabazitaxel therapy than with Lu-PSMA (54% vs 35%, respectively). Only 1 treatment discontinuation because of adverse events was reported in the Lu-PSMA arm versus 3 in the cabazitaxel arm.

Increased Enthusiasm

“Results of TheraP support increased enthusiasm for the promise of Lu-PSMA in post–androgen receptor inhibitor, post–docetaxel metastatic CRPC,” noted David R. Wise, MD, PhD, Attending, Genitourinary Medical Oncology, Perlmutter Cancer Center, NYU Langone Health, New York, NY, who discussed this abstract at a highlights session.

“We await the results of the phase 3 VISION trial for more evidence about this new agent,” he added.

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Last modified: August 30, 2021