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Sequential [177Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study

Background: Lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 improves survival and quality of life in patients with metastatic castration-resistant prostate cancer, but whether it confers a benefit in hormone-sensitive disease is unknown. We aimed to evaluate [177Lu]Lu-PSMA-617 before docetaxel treatment in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer.

Methods: UpFrontPSMA was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 11 Australian hospitals. Eligible patients had prostate adenocarcinoma without clinically significant neuroendocrine differentiation or small-cell histology, were aged 18 years or older, had less than 4 weeks on androgen deprivation therapy, had an Eastern Cooperative Oncology Group performance status of 0–2, and had high-volume PSMA-avid disease on [68Ga]Ga-PSMA-11 PET-CT with no major discordance on 2-[18F] fluorodeoxyglucose-PET-CT. Patients were randomly assigned (1:1) to the experimental treatment ([177Lu]Lu-PSMA-617 followed 6 weeks later by docetaxel) or standard-of-care treatment (docetaxel alone) using computer-based block randomisation with random block sizes, stratified by disease volume by conventional imaging and duration of androgen deprivation therapy at the time of registration. Neither patients nor investigators were masked to treatment assignment. Patients in the experimental group received two cycles of [177Lu]Lu-PSMA-617 7·5 GBq every 6 weeks intravenously, followed 6 weeks later by six cycles of docetaxel 75 mg/m2 every 3 weeks intravenously, whereas patients in the standard-of-care treatment group received six cycles of docetaxel 75 mg/m2 every 3 weeks intravenously. All patients received continuous androgen deprivation therapy. The primary endpoint was undetectable prostate-specific antigen (≤0·2 ng/mL) at 48 weeks, assessed using a modified intention-to-treat analysis. The trial is registered with ClinicalTrials.gov, NCT04343885.

Findings: Between May 5, 2020, and April 18, 2023, 130 patients were randomly assigned, 63 (48%) to [177Lu]Lu-PSMA-617 plus docetaxel and 67 (52%) to docetaxel alone. All patients were male and no race or ethnicity data were collected. Median follow-up was 2·5 years (IQR 1·8–3·0). Four patients in the docetaxel alone group withdrew consent after randomisation and no data beyond screening were collected. An additional four patients were not evaluable for the primary endpoint at 48 weeks (two in each group). 25 (41%) of 61 patients (95% CI 30–54) in the [177Lu]Lu-PSMA-617 plus docetaxel group had undetectable PSA at 48 weeks compared with ten (16%) of 61 patients (9–28) in the docetaxel alone group (OR 3·88, 95% CI 1·61–9·38; p=0·0020). The most common grade 3 or 4 treatment-related adverse events were febrile neutropenia (seven [11%] of 63 patients in the [177Lu]Lu-PSMA-617 plus docetaxel group vs six [10%] of 63 patients in the docetaxel alone group) and diarrhoea (four [6%] of 63 patients vs none). Serious adverse events occurred in 16 (25%) patients in the [177Lu]Lu-PSMA-617 plus docetaxel group (none were definitely related to [177Lu]Lu-PSMA-617) and 16 (25%) patients in the docetaxel alone group. No treatment-related deaths occurred.

Interpretation: [177Lu]Lu-PSMA-617 followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects. Our data potentially support a role for [177Lu]Lu-PSMA-617 in metastatic hormone-sensitive prostate cancer.

Arun A Azad, PhDa,b,e ∙ Mathias Bressel, MScc,e ∙ Hsiang Tan, MBBSh,j ∙ Mark Voskoboynik, MBBSk,m ∙ Aneta Suder, MBChBn ∙ Andrew J Weickhardt, DMedSco,q ∙ Alexander Guminski, PhDr ∙ Roslyn J Francis, PhDt,v ∙ Javad Saghebi, MBBSb,e ∙ Nattakorn Dhiantravan, MBBSx ∙ Prof Anthony M Joshua, PhDy,z ∙ Prof Louise Emmett, MBBSz,aa,ab ∙ Prof Lisa Horvath, PhDac,ad ∙ Prof Declan G Murphy, MCChBb,d,e ∙ Edward Hsiao, MBChBs ∙ Bavanthi Balakrishnar, MBBSae ∙ Peter Lin, MBBSaf ∙ Andrew Redfern, MBChBv,ag ∙ William Macdonald, MBBSv,ah ∙ Siobhan Ng, MBBSu,w ∙ Prof Sze-Ting Lee, PhDf,g,p,q ∙ David A Pattison, MBBSx,ai ∙ David Nadebaum, MBBSl ∙ Ian D Kirkwood, MBBSi,j ∙ Prof Michael S Hofman, MBBSb,e on behalf of the UpFrontPSMA Study Team

  1. Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  2. Prostate Cancer Theranostics and Imaging Centre of Excellence, Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Medicine, University of Melbourne, Melbourne, VIC, Australia
  7. Department of Surgery, University of Melbourne, Melbourne, VIC, Australia
  8. Department of Medical Oncology, Royal Adelaide Hospital, Adelaide, SA, Australia
  9. Department of Nuclear Medicine and PET, Royal Adelaide Hospital, Adelaide, SA, Australia
  10. Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
  11. Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
  12. Department of Nuclear Medicine and PET, Alfred Health, Melbourne, VIC, Australia
  13. School of Translational Medicine, Monash University, Melbourne, VIC, Australia
  14. Department of Medical Oncology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
  15. Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, VIC, Australia
  16. Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, Australia
  17. School of Cancer Medicine, La Trobe University, Melbourne, VIC, Australia
  18. Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
  19. Department of Nuclear Medicine and PET, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
  20. Department of Nuclear Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
  21. Department of Oncology, Sir Charles Gairdner Hospital, Perth, WA, Australia
  22. Medical School, University of Western Australia, Perth, WA, Australia
  23. Department of Oncology, University of Western Australia, Perth, WA, Australia
  24. Department of Nuclear Medicine and Specialised PET Services, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
  25. Department of Medical Oncology, Kinghorn Cancer Centre, St Vincent's Hospital, Sydney, NSW, Australia
  26. Garvan Institute of Medical Research, Sydney, NSW, Australia
  27. Department of Theranostics and Nuclear Medicine, St Vincent's Hospital, Sydney, NSW, Australia
  28. St Vincent's Clinical School, University of New South Wales, Sydney, NSW, Australia
  29. Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia
  30. Central Clinical School, University of Sydney, Sydney, NSW, Australia
  31. Department of Medical Oncology, Liverpool Hospital, Sydney, NSW, Australia
  32. Department of Nuclear Medicine and PET, Liverpool Hospital, Sydney, NSW, Australia
  33. Department of Medical Oncology, Fiona Stanley Hospital, Perth, WA, Australia
  34. Department of Nuclear Medicine, Fiona Stanley Hospital, Perth, WA, Australia
  35. School of Medicine, University of Queensland, Brisbane, QLD, Australia
Source: Azad AA., Bressel M., Tan H. et al. Sequential [177Lu]Lu-PSMA-617 and docetaxel versus docetaxel in patients with metastatic hormone-sensitive prostate cancer (UpFrontPSMA): a multicentre, open-label, randomised, phase 2 study. The Lancet Oncology. 2024. DOI: 10.1016/S1470-2045(24)00440-6. 

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