LuPSMA Outperforms Cabazitaxel for Metastatic Castration-Resistant Prostate Cancer in Phase II Trial

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Following disease progression on docetaxel, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy reduced the risk of disease progression or death by 37% vs cabazitaxel in men with metastatic castration-resistant prostate cancer in the TheraP phase II trial reported at the 2021 Genitourinary Cancers Symposium.1 Lutetium-177–labeled PSMA-617 (LuPSMA)-treated patients had fewer toxicities and improved quality of life compared with those who received cabazitaxel. Overall survival data are not yet mature. Data were published in The Lancet to coincide with the presentation at the meeting.2

The active comparator in the trial, cabazitaxel, is considered the favored third-line therapy for metastatic castration-resistant prostate cancer following disease progression on androgen receptor–signaling agents (ie, enzalutamide and/or abiraterone) and docetaxel. If these results are confirmed in phase III trials, the data will make LuPSMA an attractive choice in this setting.

“LuPSMA is a promising alternative to cabazitaxel, with significantly higher activity, fewer grade 3 and 4 events, and similar effects on global health status and improvements in multiple patient-reported outcome domains. It represents a new class of effective therapy for men with castration-resistant prostate cancer,” said lead author Michael S. Hofman, MBBS, of Peter MacCallum Cancer Centre, Melbourne, Australia.

“LuPSMA is a promising alternative to cabazitaxel, with significantly higher activity, fewer grade 3 and 4 events, and similar effects on global health status and improvements in multiple patient-reported outcome domains.”
— Michael S. Hofman, MBBS

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LuPSMA is targeted to PSMA, a cell surface glycoprotein -expressed on metastatic prostate cancer cells but not on healthy cells. The drug delivers high levels of beta-particle radiation to PSMA-expressing cells and very low doses to healthy cells. Cabazitaxel is a semisynthetic taxane approved for treatment of castration-resistant prostate cancer following docetaxel-based treatment.

Study Details

The open-label investigator-initiated phase II TheraP trial conducted by the ANZUP Cancer Trials Group commenced recruitment in 2018 and randomly assigned 200 men 1:1 to receive -LuPSMA intravenously every 6 weeks for up to 6 cycles (starting dose of 8.5 GBq, decreasing by 0.5 GBq each cycle) vs cabazitaxel at 20 mg/m2 intravenously for up to 10 cycles. All men had metastatic castration-resistant prostate cancer and had received previous docetaxel therapy. The study was funded by the Prostate Cancer Foundation of Australia with community support from Movember, The Distinguished Gentleman’s Ride, It’s a Bloke Thing, and CAN4CANCER.

A positive gallium Ga-68–labeled PSMA positron-emission tomography/computed tomography (PET/CT) scan was used to select patients for enrollment. A negative scan excluded patients. F-18–fluorodeoxyglucose (FDG) PET/CT was also performed, and patients with discordant FDG-positive PSMA-negative sites were excluded. Of 291 patients screened, 91 were excluded. A total of 15 patients dropped out of the cabazitaxel arm during the study vs none in the LuPSMA arm.

The median age was 72 years; 91% of patients were previously treated with abiraterone, enzalutamide, or both; and about 95% had an Eastern Cooperative Oncology Group performance score of 0 or 1.

TheraP met its primary endpoint, with a higher percentage of patients receiving LuPSMA achieving a 50% or greater reduction in PSA levels from baseline compared with cabazitaxel: 66% vs 37%, respectively (P < .0001). LuPSMA treatment more than doubled the objective response rate compared with cabazitaxel: 49% vs 24%, respectively.

The median radiographic progression-free survival was similar in each arm at 5.1 months. However, at 12 months, 19% of patients treated with LuPSMA vs 3% of the cabazitaxel-treated group were progression-free by radiographic or PSA criteria. Moreover, LuPSMA treatment led to a greater reduction in pain scores after treatment, with 60% reporting improvements vs 43% in the cabazitaxel arm.

Grade 3 or 4 toxicities were reported in 33% of patients on the LuPSMA arm vs 53% of those treated with cabazitaxel. The most commonly reported grade 3 or 4 events in the LuPSMA and -cabazitaxel arms, respectively, were neutropenia (4% vs 13%), thrombocytopenia (11% vs 0%), anemia (8% in each arm), diarrhea (1% vs 5%), and fatigue (5% vs 4%).

As measured by the European Organisation for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire (QLQ-C30), LuPSMA significantly improved the domains of social functioning, fatigue, insomnia, and diarrhea and numerically improved all other domains. The incidences of skin rash, palmar/plantar soreness, dysgeusia, dizziness, urinary symptoms, and diarrhea were significantly lower in the group treated with LuPSMA than in those who received cabazitaxel.

The rate of deterioration-free survival (defined as the time to at least a 10-point deterioration on the EORTC QLQ-C30 questionnaire in global health status, disease progression, or death) was improved at both 6 and 12 months in the LuPSMA-treated group compared with cabazitaxel: 29% vs 13% at 6 months, and 21% vs 1% at 12 months.

Editorial Comment

In an accompanying editorial in The Lancet, Thomas A. Hope, MD, of the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, and Jeremie Calais, MD, of the University of California, Los Angeles, Jonsson Comprehensive Cancer Center, praised the investigators of TheraP.3

Thomas A. Hope, MD

Thomas A. Hope, MD

Jeremie Calais, MD

Jeremie Calais, MD

“The completion of this study is a considerable accomplishment, given the absence of a pharmaceutical industry sponsor. It is rare for a trial to be done in which the synthesis of the drug is done by the participating academic institutions,” they wrote.

They focused on the comparator arm as a strength of the trial. “[C]abazitaxel is an effective therapy for patients who have already received docetaxel,” they wrote, noting that other PSMA-targeted radionuclide therapy trials are using weaker comparator arms.

The progression-free survival curves of the trial began to separate in favor of LuPSMA only at 6 months. “This may be the most interesting aspect of this study and highlights two points. First, PSMA-targeted radiopharmaceutical therapy is cumulative, unlike chemotherapy. Tumor cells receive doses of radioactivity every 6 weeks, and therefore the treatment effect might not be shown immediately. Second, a subpopulation of patients exist who have a prolonged benefit from PSMA-targeted radiopharmaceutical therapy, pushing out the tail of the PSMA-targeted radiopharmaceutical therapy progression-free survival curves,” they wrote.

Publisher's Note: This article was originally published in the March 25, 2021 issue of The ASCO Post.

DISCLOSURE: Dr. Hofman has received research support from Endocyte (now a Novartis company), Australian Nuclear Science and Technology Organisation, the Prostate Cancer Foundation of Australia, and Movember during the conduct of this study; has received honoraria from Janssen, Sanofi Genzyme, Mundipharma, and Astellas; and has received research support from the Prostate Cancer Foundation. Dr. Hope has received honoraria from GE Healthcare; has served as a consultant or advisor to Curium and Ipsen; has received research funding from GE Healthcare and Philips Healthcare; has received institutional research funding from Advanced Accelerator Applications; and has been reimbursed for travel, accommodations, or other expenses by GE Healthcare. Dr. Calais has received honoraria from Advanced Accelerator Applications, Progenics, and RadioMedix; has served as a consultant or advisor to Blue Earth Diagnostics, Curium Pharma, GE Healthcare, Janssen, Point Biopharma, Progenics, and Telix; has participated in a speakers bureau for IBA and Telix; and has received research funding from Progenics.


1. Hofman MS, Emmett L, Sandhu SK, et al: 177Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer progressing after docetaxel: Updated results including progression-free survival and patient-reported outcomes (TheraP ANZUP). 2021 Genitourinary Cancers Symposium. Abstract 6. Presented February 11, 2021.

2. Hofman MS, Emmett L, Sandhu SK, et al: 177Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): A randomized, open-label, phase 2 trial. Lancet 397:797-804, 2021.

3. Hope TA, Calais J: PSMA-targeted radiopharmaceutical therapy in patients with metastatic prostate cancer. Lancet 397:768-769, 2021.

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