LBA66 - UpFrontPSMA: A randomised phase II study of sequential 177Lu-PSMA-617 and docetaxel (D) versus docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC)

Background

Androgen deprivation therapy (ADT) + D is a standard-of-care for patients (pts) with de novo high-volume mHSPC, however outcomes remain sub-optimal. ¹⁷⁷Lu-PSMA-617 (LuPSMA) has proven efficacy in metastatic castration-resistant prostate cancer, but its activity in mHSPC is unknown. We evaluated the efficacy of LuPSMA prior to D in de novo high-volume mHSPC.

Methods

We conducted an investigator-initiated, randomised, 2-arm, multi-centre, phase 2 clinical trial. Key eligibility criteria included prostate cancer diagnosed within 12 weeks of screening commencement, < 4 weeks on ADT, and high-volume (≥ 4 bone metastases with ≥ 1 outside the axial skeleton, and/or visceral metastases) PSMA-avid disease on PSMA PET/CT with no major discordance on ¹⁸FDG-PET/CT. Pts were randomized 1:1 to LuPSMA 7.5 GBq x 2 cycles followed by D (Arm A), or D alone (Arm B). All patients received ADT and D at 75mg/m2 x 6 cycles. The primary endpoint was undetectable PSA (≤ 0.2 ng/ml) at 48 weeks. Secondary endpoints included safety, freedom from castration resistance, PSA-progression-free-survival (PSA-PFS) and radiographic PFS.

Results

130 patients were randomised between April 2020 and April 2023 (Arm A: 63, Arm B: 67). 4 patients in Arm B withdrew after randomisation and 2 pts in each arm were not assessable at 48 weeks. All pts in Arm A received 2 cycles LuPSMA. 50/63 (79%) and 53/63 (84%) received 6 cycles of D in Arm A and Arm B, respectively. Undetectable PSA rates at 48 weeks were higher in Arm A vs Arm B: 41% (25/61) vs 16% (10/61), odds ratio 3.9 (95% CI 1.6-9.4), p=0.002. PSA-PFS (median 30 vs 21 months; hazard ratio (HR) 0.60 (95% CI: 0.4-1.0); p=0.039), freedom from castration-resistance (median 20 vs 16 months; HR 0.60 (95% CI: 0.4-1.0); p=0.033) and radiographic PFS (median not reached vs 22 months; HR 0.58 (95% CI: 0.3-1.0); p=0.067) were all longer in Arm A versus Arm B. Grade 3 or 4 adverse events occurred in 29% (18/63) and 27% (17/63) of patients in Arm A and Arm B respectively, typically attributable to D.

Conclusions

Sequential use of LuPSMA followed by D improved clinical outcomes in de novo high-volume mHSPC compared to D alone, without increased toxicity. Our data support a role for LuPSMA in patients with mHSPC.

Clinical trial identification

NCT04343885.

Editorial acknowledgement

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

Movember Australia, Medical Research Future Fund, Novartis, University of Melbourne, Victorian Cancer Agency, Congressionally Directed Medical Research Program (CDRMP) of the USA Department of Defence, Peter MacCallum Cancer Foundation.

Disclosure

A.A. Azad: Financial Interests, Personal, Advisory Board: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dohme, Daiichi Sankyo, Arvinas; Financial Interests, Personal, Other, Consultant: Aculeus Therapeutics; Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb, Merck Serono, Bayer; Financial Interests, Personal, Other, Travel + Accommodation: Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer, Bayer; Financial Interests, Personal, Research Grant: Astellas, Merck Serono, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Astellas, Pfizer, Exelixis; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Aptevo Therapeutics, AstraZeneca, GSK, Pfizer, Astellas, SYNthorx, Bionomics, Sanofi, Ipsen, Exelixis, Merck Sharpe Dohme, Janssen, Eli Lilly, Gilead Sciences, Merck Serono, Hinova; Financial Interests, Institutional, Trial Chair: Bayer; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Hinova; Financial Interests, Personal, Trial Chair: Janssen, AstraZeneca; Non-Financial Interests, Leadership Role, Chair, Translational Research Committee: ANZUP Cancer Trials Group; Non-Financial Interests, Leadership Role, Member, Scientific Advisory Committee: ANZUP Cancer Trials Group; Non-Financial Interests, Leadership Role, Chair, Urologic Oncology Committee: Clinical Oncology Society of Australia; Non-Financial Interests, Other, Editorial Board Member: BMC Urology; Non-Financial Interests, Other, Associate Editor: Cancer Research Communications, Frontiers in Oncology. M. Voskoboynik: Financial Interests, Personal, Advisory Board: AstraZeneca, MSD, Onko-innate; Financial Interests, Personal, Other, Consulting Role: PSI-CRO; Financial Interests, Institutional, Local PI: AstraZeneca, MSD, Alpine Immune Sciences, Virocure, Hinova Pharmaceuticals, Atridia, Antengene, BeiGene, Hengrui Pharmaceutical, Multitude Therapeutics, Anwita Biosciences, Pharmabcine, Immunocore. A.J. Weickhardt: Financial Interests, Personal, Advisory Board: Merck, Ipsen, Pfizer; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Coordinating PI, PCR MIB funding: Merck. A. Guminski: Financial Interests, Personal, Advisory Board: Regeneron, MSD, Pfizer, Merck KgA; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Institutional, Other, Supply of drug for an investigator initiated clinical trial: AstraZeneca; Financial Interests, Institutional, Other, Drug and genomic testing support for an investigator initiated clinical trial: Sun Pharma; Non-Financial Interests, Advisory Role, Clinical Trial Steering Committee: Shasqi. R.J. Francis: Financial Interests, Institutional, Other, Consultancy activities: AIQ Solutions; Financial Interests, Personal, Stocks/Shares, Declaration relates to family member: AIQ Solutions; Financial Interests, Institutional, Funding, Collaborative research agreement between academic research institution and AIQ Solutions: AIQ Solutions. A. Joshua: Financial Interests, Personal, Stocks or ownership: Pricilium Therapeutics, Opthea; Financial Interests, Institutional, Advisory Board: Janssen, Ipsen, AstraZeneca, Sanofi, Pfizer, Novartis, Merck Serono, Eisai, Ideaya, IQvia, Bayer, Astellas, Grey Wolf Therapeutics, Medison, Starpharma; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Janssen, MSD, Mayne Pharma, Roche, Bayer, Lilly, Pfizer, AstraZeneca, Corvus Pharmaceuticals, Lilly; Financial Interests, Personal, Royalties: Cancer therapeutic methods. L. Emmett: Financial Interests, Personal, Invited Speaker: AstraZeneca, telix; Financial Interests, Institutional, Invited Speaker: Astellas; Financial Interests, Personal, Advisory Board: Clarity Pharma; Financial Interests, Institutional, Research Grant, supplemental trial support for ENZAp: Novartis; Financial Interests, Institutional, Coordinating PI, Trial support: Clovis. D. Murphy: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Bayer, AstraZeneca, Mundipharma, Cipla, Novartis, Ipsen, Device Technologies. D.A. Pattison: Financial Interests, Personal, Invited Speaker, Independent educational presentation on thyroid cancer: Eisai; Financial Interests, Personal, Advisory Board: Ipsen. I.D. Kirkwood: Financial Interests, Institutional, Stocks/Shares: Sonic Healthcare, Resmed, CSL. M.S. Hofman: Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Research Grant: Novartis, Isotopia Molecular Imaging, Bayer; Other, Research Support: Movember, Prostate Cancer Foundation (PCF), Prostate Cancer Foundation of Australia (PCFA). All other authors have declared no conflicts of interest.