[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial

Louise Emmett; Shalini Subramaniam; Megan Crumbaker; Andrew Nguyen; Anthony M Joshua; Andrew Weickhardt; Sze-Ting Lee; Siobhan Ng; Roslyn J Francis; Jeffrey C Goh; David A Pattison; Thean Hsiang Tan; Ian D Kirkwood; Craig Gedye; Natalie K Rutherford; Shahneen Sandhu; Aravind Ravi Kumar; David Pook; Shakher Ramdave; David P Nadebaum; Mark Voskoboynik; Andrew D Redfern; William Macdonald; Laurence Krieger; Geoff Schembri; Wei Chua; Peter Lin; Lisa Horvath; Patricia Bastick; Patrick Butler; Alison Yan Zhang; Sonia Yip; Hayley Thomas; Ailsa Langford; Michael S Hofman; Margaret McJannett; Andrew James Martin; Martin R Stockler; Ian D Davis; ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

doi:10.1016/S1470-2045(24)00135-9

[¹⁷⁷Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial

Lancet Oncol. 2024 May;25(5):563-571. doi: 10.1016/S1470-2045(24)00135-9. Epub 2024 Apr 12.

Authors

Louise Emmett¹, Shalini Subramaniam², Megan Crumbaker³, Andrew Nguyen⁴, Anthony M Joshua⁵, Andrew Weickhardt⁶, Sze-Ting Lee⁷, Siobhan Ng⁸, Roslyn J Francis⁹, Jeffrey C Goh¹⁰, David A Pattison¹¹, Thean Hsiang Tan¹², Ian D Kirkwood¹³, Craig Gedye¹⁴, Natalie K Rutherford¹⁵, Shahneen Sandhu¹⁶, Aravind Ravi Kumar¹⁷, David Pook¹⁸, Shakher Ramdave¹⁹, David P Nadebaum²⁰, Mark Voskoboynik²¹, Andrew D Redfern²², William Macdonald²³, Laurence Krieger²⁴, Geoff Schembri²⁵, Wei Chua²⁶, Peter Lin²⁷, Lisa Horvath²⁸, Patricia Bastick²⁹, Patrick Butler³⁰, Alison Yan Zhang³¹, Sonia Yip³², Hayley Thomas³², Ailsa Langford³², Michael S Hofman¹⁶, Margaret McJannett³³, Andrew James Martin³⁴, Martin R Stockler³⁵, Ian D Davis³⁶; ENZA-p Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group

Affiliations

¹ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia. Electronic address: [email protected].
² NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Bankstown-Lidcombe Hospital, Sydney, NSW, Australia.
³ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia; Macquarie University Hospital, Sydney, NSW, Australia.
⁴ Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia; St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia.
⁵ Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia; Garvan Institute of Medical Research, Sydney, NSW, Australia.
⁶ Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia.
⁷ Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia; Olivia Newton-John Cancer Research Institute, Melbourne, VIC, Australia; Department of Medicine and Department of Surgery, University of Melbourne, Melbourne, VIC, Australia.
⁸ Department of Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia; Department of Oncology, University of Western Australia, Perth, WA, Australia.
⁹ Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia; Medical School, University of Western Australia, Perth, WA, Australia.
¹⁰ Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Queensland University of Technology, Brisbane, QLD, Australia.
¹¹ Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; School of Medicine, University of Queensland, Brisbane, QLD, Australia.
¹² Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia.
¹³ Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, SA, Australia; Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, Australia.
¹⁴ Department of Medical Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia.
¹⁵ Department of Nuclear Medicine, Hunter New England Health, Newcastle, NSW, Australia.
¹⁶ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia; Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁷ Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
¹⁸ Department of Oncology, Monash Health, Melbourne, VIC, Australia.
¹⁹ Monash Health Imaging, Monash Health, Melbourne, VIC, Australia.
²⁰ Department of Oncology, Alfred Health, Melbourne, VIC, Australia.
²¹ Department of Oncology, Alfred Health, Melbourne, VIC, Australia; Central Clinical School, Monash University, Melbourne, VIC, Australia.
²² Medical School, University of Western Australia, Perth, WA, Australia; Department of Medical Oncology, Fiona Stanley Hospital, Perth, WA, Australia.
²³ Medical School, University of Western Australia, Perth, WA, Australia; Department of Nuclear Medicine, Fiona Stanley Hospital, Perth, WA, Australia.
²⁴ Genesis Care North Shore, Sydney, NSW, Australia.
²⁵ Nuclear Medicine, Royal North Shore Hospital, Sydney, NSW, Australia.
²⁶ Department of Medical Oncology, Liverpool Hospital, Sydney, NSW, Australia; Western Sydney University, Sydney, NSW, Australia.
²⁷ South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia; Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, NSW, Australia.
²⁸ Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
²⁹ Department of Medical Oncology, St George Hospital, Sydney, NSW, Australia.
³⁰ Department of Nuclear Medicine, St George Hospital, Sydney, NSW, Australia.
³¹ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Macquarie University Hospital, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
³² NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
³³ Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Sydney, NSW, Australia.
³⁴ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Centre for Clinical Research, University of Queensland, Brisbane, QLD, Australia.
³⁵ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia.
³⁶ Monash University Eastern Health Clinical School, Melbourne, VIC, Australia; Eastern Health, Melbourne, VIC, Australia.

PMID: 38621400
DOI: 10.1016/S1470-2045(24)00135-9

Abstract

Background: Enzalutamide and lutetium-177 [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [¹⁷⁷Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer.

Methods: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [⁶⁸Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [¹⁷⁷Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing.

Findings: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [¹⁷⁷Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group.

Interpretation: The addition of [¹⁷⁷Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer.

Funding: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Publication types

Research Support, Non-U.S. Gov't
Randomized Controlled Trial
Multicenter Study
Clinical Trial, Phase II

MeSH terms

Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
Benzamides*
Dipeptides* / administration & dosage
Dipeptides* / adverse effects
Dipeptides* / therapeutic use
Heterocyclic Compounds, 1-Ring* / administration & dosage
Heterocyclic Compounds, 1-Ring* / adverse effects
Heterocyclic Compounds, 1-Ring* / therapeutic use
Humans
Lutetium*
Male
Middle Aged
Nitriles*
Phenylthiohydantoin* / administration & dosage
Phenylthiohydantoin* / analogs & derivatives
Phenylthiohydantoin* / therapeutic use
Progression-Free Survival
Prostate-Specific Antigen / blood
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / mortality
Prostatic Neoplasms, Castration-Resistant* / pathology
Radioisotopes / therapeutic use
Radiopharmaceuticals

Substances

Phenylthiohydantoin
Benzamides
enzalutamide
Nitriles
Lutetium
Dipeptides
Heterocyclic Compounds, 1-Ring
PSMA-617
Prostate-Specific Antigen
Lutetium-177
Radioisotopes
Radiopharmaceuticals

Associated data

ClinicalTrials.gov/NCT04419402