LBA84 - Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): A randomised, phase II trial: ENZA-p (ANZUP 1901)

Background

Enzalutamide (ENZA) and Lutetium-177-prostate-specific membrane antigen-617 (LuPSMA) both improve overall survival (OS) in mCRPC. Preclinical and clinical data suggest synergy for LuPSMA with androgen receptor pathway inhibitors (ARPI) in mCRPC. We evaluated the activity and safety of combining ENZA with adaptive-dosing of LuPSMA vs ENZA alone as first-line treatment for mCRPC.

Methods

Participants (pts) had mCRPC not previously treated with chemotherapy or ARPI (prior abiraterone and/or docetaxel for hormone-sensitive disease were allowed), ⁶⁸Ga-PSMA-positive disease on positron emission tomography (PET), and at least 2 risk factors associated with early progression on ENZA. Pts were randomised (1:1) to either ENZA 160 mg daily (ENZA-alone), or ENZA 160 mg daily plus adaptive dosing LuPSMA 7.5 GBq on days 15 and 57, with 2 further doses of LuPSMA if persistent PSMA-positive disease on interim ⁶⁸Ga-PSMA PET (day 92) (ENZA+LuPSMA). The primary endpoint was PSA-progression free survival (PSA-PFS). Secondary endpoints include radiological PFS (rPFS), PSA50% and PSA90% response rates (PSA50RR, PSA90RR), adverse events (AE), and OS.

Results

We randomised 162 pts from Aug 2020 to Jul 2022: median age 71 (range 45-96), prior docetaxel in 54%, and prior abiraterone in 13%. Imaging screen failure rate was 18% (40/220). 16% (13) of pts received between 2-3 doses of LuPSMA and 81% (67) received 4 doses. The median follow up was 20 months (IQR 18-21). PSA-PFS was longer with ENZA+LuPSMA vs ENZA-alone (median 13 vs 7.8 months; HR 0.43 [95%CI 0.29-0.63], p<0.001). PSA50RR and PSA90RR were higher with ENZA+LuPSMA vs ENZA-alone: 93% (77/83) vs 68% (54/79) (p<0.001) and 78% (65/83) vs 37% (29/79) (p<0.001) respectively. Analysis of rPFS (ongoing) will be presented. SAE were reported in 33% (27/81) of pts assigned ENZA+LuPSMA vs 35% (28/79) ENZA-alone.

Conclusions

The addition of adaptive-dosing of LuPSMA (2-4 doses) to ENZA improved PSA-PFS, PSA50RR, and PSA90RR. Our data supports enhanced anti-cancer activity with the use of adaptive-dosed LuPSMA together with ENZA as first-line treatment in mCPRC.

Clinical trial identification

NCT04419402.

Editorial acknowledgement

Legal entity responsible for the study

ANZUP Cancer Trials Group Limited.

Funding

Prostate Cancer Research Alliance (PCRA), Movember Foundation, Cancer Australia, Endocyte – a Novartis company, Astellas, Australasian Radiopharmaceutical Trials Network (ARTnet), St Vincent’s Clinic Foundation, Roy Morgan Research, GenesisCare, Australian Nuclear Science and Technology Organisation (ANSTO) and MIM Software

Disclosure

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: Novartis; Financial Interests, Institutional, Coordinating PI: Clovis. M. Crumbaker: Non-Financial Interests, Advisory Role, 1 off advisory board meeting - March 2023: Astellas. A.M. Joshua: Financial Interests, Personal, Stocks/Shares: Pricillium Therapeutics; Financial Interests, Institutional, Local PI, No financial interest: AstraZeneca, BMS, Eisai, Ipsen, Janssen, Merck Serono, Neolukin, Novartis, Noxopharm, Pfizer, Sanofi; Financial Interests, Institutional, Steering Committee Member, No financial interest: Iqvia; Non-Financial Interests, Advisory Role: AstraZeneca, Bayer, BMS, Corvus, Eli-Lilly, Janssen, Macrogenics, Mayne, Merck, Pfizer, Roche. 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. R.J. Francis: Financial Interests, Institutional, Other, Consultancy activities: AIQ Solutions; Financial Interests, Personal, Stocks/Shares, Declaration relates to family member (spouse): AIQ Solutions; Financial Interests, Institutional, Funding, Collaborative research agreement between University of Western Australia and AIQ Solutions.: AIQ Solutions. J.C.H. Goh: Financial Interests, Personal, Advisory Board, Prior member of the BMS RCC Advisory Board: BMS; Financial Interests, Personal, Advisory Board, Uterine Cancer Advisory Board: GSK; Financial Interests, Personal, Other, Chairing RCC meeting: Ipsen; Financial Interests, Personal, Invited Speaker, Speaking @ MSD sponsored event on Gynaecological cancerSpeaking at MSD sponsored event on RCC: MSD; Financial Interests, Personal, Advisory Board, Met RCC Advisory Board: MSD/ Eisai; Financial Interests, Personal, Other, 1. Asia-Pacific Advisory Board member for prostate cancer2. Invited Speaker at AZ sponsored molecular/genomic testing meeting: AstraZeneca; Financial Interests, Personal, Stocks/Shares, Private Cancer Centres in Australia: ICON Cancer Centres; Financial Interests, Institutional, Funding, Funding for phase 2 metastatic cervical cancer trial: BeiGene; Non-Financial Interests, Principal Investigator, local PI for CHECKMATE-914, CHECKMATE-9KD trial, CHECKMATE-7DX & CHECKMATE-9ER trials: BMS. 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. S.K. Sandhu: Financial Interests, Institutional, Advisory Board, I have served on advisory boards for BMS. The contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Bristol Myer Squib; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for MSD. The e contracts for my role are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Merck Sharp and Dohme; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for AstraZeneca. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: AstraZeneca; Financial Interests, Institutional, Advisory Board, I have served on advisory boards for Novartis. The contracts for my role as an advisor are set up with the institution and the funds go to a research fund at Peter MacCallum Cancer Centre.: Novartis; Financial Interests, Institutional, Advisory Board, I have served on an advisory board for Merck Serono. The contracts for my service are set up with the institution and funds go into a research fund at the Peter MacCallum Cancer Centre.: Merck Serono; Financial Interests, Institutional, Research Grant, My institution receives grant funding to run an investigator initiated trial that I lead.: Novartis, Genentech, Amgen, AstraZeneca, Merck Serono, Merck Sharp and Dohme; Financial Interests, Institutional, Funding, Pfizer are providing funding to my institution for the conduct of an investigator initiated clinical trial.: Pfizer; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Janssen sponsored studies and don't receive any renumeration for this.: Janssen; Non-Financial Interests, Principal Investigator, I am a principal investigator on several Novartis sponsored studies and dont receive any renumeration for this.: Novartis; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Genentech sponsored studies and don't receive any renumeration for this.: Genentech; Non-Financial Interests, Principal Investigator, I am a principal investigator on several of Bristol Myer Squibb sponsored studies and don't receive any renumeration for this.: Bristol Myer Squibb; Non-Financial Interests, Other, I serve on the Independent Safety and Data Monitoring committee for 2 of Novartis sponsored studies and don’t receive any compensation for this.: Novartis; Non-Financial Interests, Principal Investigator, I am the Principal Investigator for several AstraZeneca sponsored studies and am not remunerated for this.: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for several Janssen sponsored trials and i do not receive compensation for this.: Janssen; Non-Financial Interests, Other, I serve on the steering committee for one AstraZeneca sponsored trial and I do not receive compensation for this.: AstraZeneca; Non-Financial Interests, Other, I serve on the steering committee for one Genentech sponsored trials and I do not receive compensation for this.: Genentech; Non-Financial Interests, Other, I serve on the steering committee for a Bristol Myer Squibb sponsored trial and I do not receive renumeration for this.: Bristol Myer Squibb. C. Gedye: Financial Interests, Personal, Advisory Board: Cadex Genomics, BCAL Diagnostics; Financial Interests, Institutional, Coordinating PI: Bristol Myers Squibb, Amgen, Merck Sharpe Dohme; Financial Interests, Institutional, Steering Committee Member: Ipsen. M. 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). M.R. Stockler: Financial Interests, Institutional, Research Grant, DASL: Bayer; Financial Interests, Institutional, Research Grant, ENZAMET & ENZARAD: Astellas; Financial Interests, Institutional, Research Grant, KEYPAD: Amgen, MSD; Financial Interests, Institutional, Research Grant, NIVORAD: BMS; Financial Interests, Institutional, Research Grant: Pfizer, Roche; Financial Interests, Institutional, Research Grant, ADELE: BeiGene; Financial Interests, Institutional, Research Grant, PARAGON2: Novartis; Financial Interests, Institutional, Other, Study Drug for Cannabis CINV Trial: Tilray. I.D. Davis: Financial Interests, Personal, Full or part-time Employment, Professor of Medicine and Head of Eastern Health Clinical School: Monash University; Financial Interests, Personal, Full or part-time Employment, Professor of Medicine; Head, Eastern Health Clinical School; medical oncologist: Eastern Health; Financial Interests, Personal, Royalties, Authorship royalties for: Health Press; Financial Interests, Personal, Other, Remuneration for associate editor role in Therapeutic Advances in Medical Oncology: SAGE; Financial Interests, Institutional, Local PI, Institutional support for clinical research: Movember Foundation, Merck/MSD, Bristol Myers Squibb, Exelixis, Astellas, Pfizer, AstraZeneca, Roche / Genentech, Eisai, Bayer, Janssen, Ipsen, Seagen; Non-Financial Interests, Member of Board of Directors, Director and Chair: ANZUP Cancer Trials Group; Non-Financial Interests, Advisory Role, All honoraria and payments are made directly to ANZUP Cancer Trials Group with no pass-through payment: Roche, Eisai, Pio Therapeutics, Xennials Therapeutics, Telix Therapeutics; Non-Financial Interests, Other, Member of Council: Clinical Oncology Society of Australia; Non-Financial Interests, Member: ASCO, Clinical Oncology Society of Australia, Medical Oncology Group of Australia, American Association for Cancer Research, Australian Academy of Health and Medical Sciences. All other authors have declared no conflicts of interest.