LuPSMA Improves Progression-Free Survival vs Cabazitaxel in PSMA-Positive Metastatic Castration-Resistant Prostate Cancer

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Lutetium-177–labeled PSMA-617 (LuPSMA; lutetium Lu 177 vipivotide tetraxetan) achieved longer progression-free survival with fewer toxicities compared with cabazitaxel in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer whose disease progressed after treatment with docetaxel and an androgen receptor pathway inhibitor. At this point in time (36 months of follow-up), overall survival is similar for both treatments.1

These findings of the randomized, open-label phase II TheraP trial, presented at the 2022 ASCO Annual Meeting, suggest that LuPSMA represents an improved third-line option over cabazitaxel for patients with PSMA-positive disease progression on docetaxel and an androgen receptor pathway inhibitor, mainly because of its effect on progression-free survival, low toxicity profile, and improvements in patient-reported outcomes.

At a median of 36 months of follow-up, there was no statistically significant or clinically meaningful difference in overall survival between the LuPSMA arm and the cabazitaxel arm. Treatment with LuPSMA significantly improved progression-free survival compared with cabazitaxel. Updated median progression-free survival was 7.1 months with LuPSMA vs 5 months with cabazitaxel, representing a 38% reduction in the risk of disease progression or death (P = .0028).

Michael S. Hofman, MBBS

Michael S. Hofman, MBBS

“TheraP supports the choice of [LuPSMA] over cabazitaxel for patients with PSMA PET–positive progressive metastatic castration-resistant prostate cancer after treatment with docetaxel and an androgen receptor pathway inhibitor, on the basis of its higher prostate-specific antigen response rate, greater progression-free survival benefit, quality-of-life benefits, favorable safety profile and dosing schedule, and similar survival outcomes,” stated lead author Michael S. Hofman, MBBS, Director of the Prostate Cancer Theranostics and Imaging Centre of Excellence at the Peter MacCallum Cancer Centre, Melbourne. “Survival was considerably shorter for patients excluded on PSMA/FDG-PET [fluorodeoxyglucose (F-18) positron-emission tomography] with either low PSMA expression or PSMA-discordant disease.”

LuPSMA is a radioligand that targets PSMA, which is expressed almost exclusively by metastatic prostate cancer cells but is not present in all metastatic prostate cancer cells. Previously, the VISION trial showed that LuPSMA plus the standard of care significantly improved radiographic progression–free survival and overall survival in 831 men with PSMA-positive metastatic castration-resistant prostate cancer compared with the standard of care. All men received previous treatment with a taxane and androgen receptor pathway inhibitor.2

TheraP is the first randomized controlled trial comparing LuPSMA with the standard third-line option for metastatic castration-resistant prostate cancer, cabazitaxel, but it is a smaller trial than VISION. Primary results of TheraP were previously published.3 At the ASCO meeting, Dr. Hofman presented the trial’s secondary endpoint of overall survival.

Study Details

TheraP enrolled a total of 291 men with metastatic castration-­resistant prostate cancer following docetaxel treatment who had a rising prostate-specific antigen (PSA) and a PSA level ≥ 20 ng/mL. All men underwent PET imaging with gallium-68–PSMA-11 and were required to have high PSMA expression. Patients with FDG-positive/PSMA-negative disease sites (discordant disease) were excluded.

Of the 291 patients screened, 200 were eligible for inclusion and were randomly assigned at a 1:1 ratio to receive treatment with either LuPSMA at 8.5 GBq every 6 weeks for a maximum of 6 cycles (n = 99), or cabazitaxel at 20 mg/m2 every 3 weeks for a maximum of 10 cycles (n = 101). A total of 15 men withdrew from the trial postrandomization.

In the previously published analysis of TheraP, responses and secondary endpoints were all improved with LuPSMA.3 By 12 months, progression-free survival was 19% in the LuPSMA arm, compared with 3% in the cabazitaxel arm. A PSA reduction of 50% or more from baseline occurred more frequently in the LuPSMA arm vs the cabazitaxel arm: 66% vs 37%, respectively, reflecting a 29% improvement for LuPSMA that was statistically significant (P < .0001). The objective response rate was 49% vs 24%, respectively. Grade 3 and 4 toxicities were 33% in the LuPSMA arm vs 53% in the cabazitaxel arm.

At a median follow-up of 36 months, deaths were reported in 70 of 101 patients receiving cabazitaxel, 77 of 99 patients receiving LuPSMA, and 55 of 61 patients excluded after PSMA/FDG-PET screening.1 

Post protocol, patients had access to cabazitaxel, LuPSMA, abiraterone acetate, and enzalutamide. Of the patients randomly assigned to LuPSMA, 32% went on to receive cabazitaxel, and 5% received additional LuPSMA. In the cabazitaxel arm, 21% of patients received additional cabazitaxel, and 20% received LuPSMA.

Overall survival was also evaluated in the patients who were excluded due to screening failure; 61 of 80 patients consented to follow-up. The next line of treatment for these patients was cabazitaxel (48%), enzalutamide (7%), LuPSMA (5%), carboplatin (5%), other (5%), and mitoxantrone (2%). Overall survival was 18.8 months in the randomly assigned patients vs 11.0 months in the patients with PSMA/FDG-PET screening failure.

Clinical Implications of TheraP

Dr. Hofman said the strengths of the study included its prospective, randomized, multicenter design, the fact that it had 3 years of follow-up, and that it had an active control arm. Limitations included the fact that postprotocol crossover confounded detection of a difference in overall survival.

 “TheraP was not powered to detect a difference in overall survival, and this is also significant with regard to withdrawals in the cabazitaxel arm in patients seeking to have LuPSMA therapy, which did not occur in the LuPSMA arm,” he elaborated.

“The clinical implications are that LuPSMA has similar overall survival to cabazitaxel, a proven life-prolonging therapy, but with fewer adverse events and better patient-reported outcomes. However, we should be clear that LuPSMA shows greater activity, and that is not just confined to PSA response rates, because we see it with radiographic progression-free survival and RECIST,” Dr. Hofman stated.

With additional follow-up, no new safety signals were reported. 

Regarding patient selection, Dr. Hofman said the odds of PSA response were higher when PSMA positivity was used as a predictive marker, but they were almost six times higher using PSA progression. “So, PSA progression should be prioritized,” he told listeners.

Earlier this year, the U.S. Food and Drug Administration approved LuPSMA for the treatment of adults with PSMA-positive metastatic castration-resistant prostate cancer previously treated with other anticancer therapies, including androgen receptor pathway inhibition and taxane-based chemotherapy.

Comment on Study

Oliver Sartor, MD

Oliver Sartor, MD

In a separate interview, Oliver Sartor, MD, Medical Director of the Tulane Cancer Center in New Orleans, weighed in on the TheraP results in context with the VISION trial, for which he was principal investigator.

“One of the main differences between the two trials were the control arms. In VISION, the majority were treated in the control arm with an alternative hormone therapy [ie, enzalutamide, abiraterone], whereas TheraP used cabazitaxel as the control arm. Cabazitaxel is known to be a life-prolonging therapy. So, lesson number one from TheraP is that cabazitaxel is a very effective drug,” he said.

“There was not much information on radiographic progression–free survival in TheraP, but for PSA progression, LuPSMA looked better. It’s plausible that cabazitaxel performed better than expected, whereas LuPSMA performed as expected. In the end, there was no difference in overall survival,” Dr. Sartor continued.

“LuPSMA has fewer toxicities, and the quality of life is better than with cabazitaxel. If you can achieve a similar outcome with fewer side effects, this would be the preferred therapy,” he stated.

Dr. Sartor noted that retreatment with LuPSMA on disease progression was not allowed in TheraP. “I think this is an area that needs further exploration. There is evidence that retreatment [with LuPSMA] may be of benefit.” 

Susan Slovin, MD, PhD

Susan Slovin, MD, PhD

Invited discussant Susan Slovin, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York, pointed out there are no relevant serum biomarkers for disease progression and the challenges of interpreting response in metastatic castration-resistant prostate cancer. “We should have more definitive criteria and biomarkers that allow us to report PSMA PET [prostate-specific membrane antigen positron-emission tomography] responses in a more consistent manner,” she stated.

“We are trying to look at differences in response with the mean SUV [standardized uptake value]. How do you capture response if there is a greater response in one lesion than another? We are learning how to classify the interpretation of PET ligands. Not every lesion in prostate cancer is PSMA-avid. Patients can have low or minimal PSMA expression,” she said.

“In Dr. Hofman’s abstract, the most interesting finding is that at the 20-month mark, there is no difference in overall survival in the intent-to-treat population. It is still difficult to choose [a treatment at disease progression] among a sea of life-prolonging therapies. For LuPSMA [lutetium-177–labeled PSMA-617], we have only 3 years of follow-up. Many questions remain, including the benefit of radiographic progression-free survival vs overall survival and what clinical state is advised for treatment [with LuPSMA]-minimal disease vs multiple disease sites.”

DISCLOSURE: Dr. Hofman has served as a consultant or advisor to Endocyte, Janssen, and POINT Biopharma; served on a speakers bureau with Astellas Pharma, AstraZeneca, Janssen, and Mundipharma; received institutional research funding from Advanced Accelerator Applications/Novartis and Endocyte; and received reimbursement for travel, accommodations, and expenses from Genzyme, Ipsen, and Janssen. Dr. Sartor reported stock or other ownership interests with AbbVie, Cardinal Health, Clarity Pharmaceuticals, Clovis Oncology, GlaxoSmithKline, Lilly, Noria Therapeutics, PSMA Therapeutics, and United Health Group; a consulting or advisory role with Advanced Accelerator Applications, ARTBIO, Astellas Pharma, AstraZeneca, Bavarian Nordic, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis Oncology, Constellation Pharmaceuticals, Dendreon, EMD Serono, Fusion Pharmaceuticals, Isotopen Technologien, Janssen, Macrogenics, Myovant Sciences, Myriad Genetics, Noria Therapeutics, Novartis, Noxopharm, Pfizer, Point Biopharma, Progenics, Ratio, Sanofi, Telix Pharmaceuticals, TeneoBio, and Theragnostics; receiving institutional research funding from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation Pharmaceuticals, Dendreon, Endocyte, InVitae, Janssen, Lantheus, Merck, Progenics, Sanofi, and SOTIO; having patents for Saposin C and receptors as targets for treatment of benign and malignant disorders (U.S. patent awarded January 23, 2007; patent no. 7,166,691); providing expert testimony for Sanofi; and receiving travel, accommodations, or expenses from ­AstraZeneca, Bayer, Johnson & Johnson, Progenics, and Sanofi. Dr. Slovin has served as a consultant or advisor to Bayer, Clovis Oncology, and Pfizer; has served on a speakers bureau for OncLive, PER, Prime Oncology, and the Society for Immunotherapy of Cancer; and has received research funding from AstraZeneca.


1.Hofman MS, Emmett L, Sandhu S, et al: TheraP: 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer progressing after docetaxel—Overall survival after median follow-up of 3 years (ANZUP 1603). 2022 ASCO Annual Meeting. Abstract 5000. Presented June 4, 2022.

2. Sartor O, de Bono J, Chi KN, et al: Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 385:1091-1103, 2021.

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