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Clinical Trial
. 2024 Sep 3;7(9):e2433863.
doi: 10.1001/jamanetworkopen.2024.33863.

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer

Yu Yang Soon  1   2   3 , Ian C Marschner  1 , Manjula Schou  1 , Michael S Hofman  4   5 , Louise Emmett  6   7 , Ian D Davis  8   9 , Martin R Stockler  1   10   11 , Andrew J Martin  1   12
Affiliations
Clinical Trial

Lu-177 PSMA vs Comparator Treatments and Survival in Metastatic Castration-Resistant Prostate Cancer

Yu Yang Soon et al. JAMA Netw Open. .

Abstract

Importance: Observed treatment effects on overall survival (OS) differed substantially in the first 2 randomized clinical trials of lutetium Lu 177 vipivotide tetraxetan (Lu-177) prostate-specific membrane antigen (PSMA) in metastatic castration-resistant prostate cancer.

Objective: To investigate factors associated with the observed difference in treatment effects on OS, including differences in the risk of crossover from randomized treatment after disease progression.

Design, setting, and participants: This comparative effectiveness study used individual participant data from 2 randomized clinical trials, TheraP (A Randomised Phase 2 Trial of 177Lu-PSMA617 Theranostic Versus Cabazitaxel in Progressive Metastatic Castration Resistant Prostate Cancer [ANZUP Protocol 1603]) (n = 200), recruited from February 2018 to September 2019 in Australia, and published data from VISION (An International, Prospective, Open Label, Multicenter, Randomized Phase 3 Study of 177Lu-PSMA-617 in the Treatment of Patients With Progressive PSMA-Positive Metastatic Castration-Resistant Prostate Cancer) (n = 831), recruited from June 2018 to October 2019 in North America and Europe. Individual participant data for OS were reconstructed from VISION using the published survival curves. Data were analyzed February 6, 2018, to December 31, 2021, for TheraP and June 4, 2018, to January 27, 2021, for VISION.

Interventions: TheraP randomized participants to receive treatment with Lu-177 PSMA or cabazitaxel. VISION randomized participants to receive treatment with or without Lu-177 PSMA in addition to physicians' choice of protocol-permitted treatments (PPT; approved hormonal treatments [such as abiraterone and enzalutamide], bisphosphonates, radiotherapy, denosumab, or glucocorticoids), excluding cabazitaxel.

Main outcomes and measures: Patient characteristics, treatment protocols, and OS outcomes of the 2 trials were compared. Estimates of the effect on OS from TheraP were adjusted for crossover from randomly assigned treatment using a rank-preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) methods.

Results: The 200 participants in TheraP and 831 participants in VISION were similar in age (median [range], 72 [49-86] vs 71 [40-94] years). Improved OS was observed in the comparator treatment group (cabazitaxel) in TheraP compared with VISION (PPT) (hazard ratio [HR], 0.53 [95% CI, 0.39-0.71]). The Lu-177 PSMA treatment groups in TheraP and VISION had similar OS (HR, 0.92 [95% CI, 0.70-1.19]). In TheraP, 20 of 101 participants in the cabazitaxel group crossed over to Lu-177 PSMA, while 32 of 99 participants in the Lu-177 PSMA arm crossed over to cabazitaxel. No statistically significant differences in OS between the Lu-177 PSMA and cabazitaxel groups of TheraP were observed after controlling for crossover to cabazitaxel: RPSFTM HR, 0.97 (95% CI, 0.60-1.58); IPCW HR, 0.92 (95% CI, 0.65-1.32); RPSFTM HR, 0.97 (95% CI, 0.60-1.58) and IPCW HR, 0.82 (95% CI, 0.54-1.24) for crossover to Lu-177 PSMA; RPSFTM HR, 0.96 (95% CI, 0.53-1.74) and IPCW HR, 0.82 (95% CI, 0.53-1.27) for crossover to either Lu-177 PSMA or cabazitaxel.

Conclusions and relevance: Findings of this secondary analysis of the TheraP and VISION randomized clinical trials suggest that the choice of comparator treatments (ie, cabazitaxel vs PPT) may explain the difference in the observed effect of Lu-177 PSMA on OS between the 2 trials. Causal inference methods such as RPSFTM and IPCW may help rule out crossover as a plausible explanation.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Soon reported receiving support from the National Medical Research Council. Dr Schou reported having stock ownership in Pfizer and Cochlear Limited. Dr Hofman reported receiving grants from Novartis (Endocyte) during the conduct of the study; receiving a clinical fellowship from the Peter MacCallum Foundation; and receiving personal fees from Janssen and MSD, and receiving grants from Bayer outside the submitted work. Dr Emmett reported receiving grants from the Movember-PCF challenge; receiving trial support from Novartis; and receiving personal fees from Clarity Pharmaceuticals, AdvanCell, and Novartis outside the submitted work. Dr Davis reported receiving a National Health and Medical Research Council investigator grant; receiving funds through his institution from Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, ESSA Pharma, Exelixis, Ipsen, Janssen Oncology, Pfizer, Movember, MSD, Roche/Genentech, and Seagen outside the submitted work; and being an unremunerated director and chair of the Australian and New Zealand Urological and Prostate (ANZUP) Cancer Clinical Trials Group. Dr Stockler reported receiving grants from Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Medivation, Novartis, Pfizer, Roche, Sanofi, and Tilray outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Swimmer Plot of Participants Randomized to Receive Treatment With Cabazitaxel Who Crossed Over to Lutetium Lu 177 Vipivotide Tetraxetan (Lu-177) PSMA Treatment and Participants Randomized To Receive Treatment With Lu-177 PSMA Who Crossed Over to Cabazitaxel Treatment
PSA indicates prostate-specific antigen.
Figure 2.
Figure 2.. Overall Survival Hazard Ratios for Estimands of Interest
HR indicates hazard ratio; IPCW, inverse probability of censoring weights; Lu-177, lutetium Lu 177 vipivotide tetraxetan; PSMA, prostate-specific membrane antigen; RPSFTM, rank-preserving structural failure time model; and SUVmean, mean standard uptake value.
Figure 3.
Figure 3.. Overall Survival for TheraP and VISION Trials
HR represents hazard ratio; Lu-177, lutetium Lu 177 vipivotide tetraxetan; PSMA, prostate-specific membrane antigen; and PPT, protocol-permitted treatment.
See this image and copyright information in PMC

References

    1. Israeli RS, Powell CT, Fair WR, Heston WD. Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res. 1993;53(2):227-230. - PubMed
    1. Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res. 1987;7(5B):927-935. - PubMed
    1. US Food and Drug Administration . FDA approval of Pluvicto (lutetium Lu 177 vipivotide tetraxetan) for the treatment of adult patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. April 22, 2022. Accessed October 18, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco...
    1. Afshar-Oromieh A, Hetzheim H, Kratochwil C, et al. The theranostic PSMA ligand PSMA-617 in the diagnosis of prostate cancer by PET/CT: biodistribution in humans, radiation dosimetry, and first evaluation of tumor lesions. J Nucl Med. 2015;56(11):1697-1705. doi: 10.2967/jnumed.115.161299 - DOI - PubMed
    1. Violet J, Jackson P, Ferdinandus J, et al. Dosimetry of 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: correlations between pretherapeutic imaging and whole-body tumor dosimetry with treatment outcomes. J Nucl Med. 2019;60(4):517-523. doi: 10.2967/jnumed.118.219352 - DOI - PubMed

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