Prostate cancer working group 4 (PCWG4) preliminary criteria using serial PSMA PET/CT for response evaluation: Analysis from the PRINCE trial

BackgroundAn expert committee of clinical investigators (the Prostate Cancer Clinical Trials Working Group 4 [PCWG4]) met in 2023 to consider a preliminary imaging criteria that incorporated PSMA PET/CT (PSMA) response assessments. Proposed criteria described complete and partial response (CR and PR), stable disease (SD) and progressive disease (PD). We sought to determine reader reproducibility and the clinical correlation of these categories using a trial dataset that incorporated 12-weekly PSMA alongside standard CT / bone scan (PCWG3) assessments.MethodsFive experienced nuclear medicine specialists independently reviewed all available PSMA PET/CT scans from the PRINCE trial (NCT03658447; 177Lu-PSMA-617 + pembrolizumab) blinded to conventional imaging response, according to draft PCWG4 criteria. Reporter agreement was measured using multilevel Fleiss Kappa. Radiographic PFS using PCWG3 and PCWG4 criteria were described, and correlated with overall survival (OS) using interactive multiple imputation for bivariate censored time-to-event data.Results36 patients with serial PSMA PET/CT and CT/bone scan were analysed (142 paired scans). 9/36 had RECIST measurable disease. Reporter agreement of PSMA PET/CT response was substantial (0.69 [95% CI: 0.61 - 0.76]) and almost perfect (0.90 [95% CI: 0.85 -0.96]) for level of response (CR, PR, SD, PD) or progression (PD vs non-PD), respectively. PCWG4 provided a level of response (CR 2, PR 7, SD 14) when PCWG3 best overall response was defined as non-PD. PCWG4 detected imaging defined progression earlier than PCWG3 with median rPFS of 9.4 (5.6-13.7) compared to 19.9 (8.2-NE) months. Correlation between PCWG4 and PCWG3 and OS was k=0.86 (95% CI: 0.71 - 0.94) and k=0.79 (95% CI: 0.58 - 0.91), respectively.ConclusionsAgreement of PSMA PET/CT response was substantial for all levels of response and almost perfect for PD vs non-PD. The criteria evaluated enable evaluation of level of response (CR, PR, SD) in patients with non-PD by PCWG3 criteria. These criteria detected progression earlier than PCWG3 that correlated well with OS. These criteria warrant consideration for PCWG4, and further validation work in a larger cohort is being undertaken.Clinical trial identificationNCT03658447 (predefined exploratory endpoint).Legal entity responsible for the studyPeter MacCallum Cancer Centre.FundingNo direct funding for this exploratory endpoint. PRINCE trial funded through Victorian Cancer Agency (VCA) with additional funding and drug supply from Merck Sharp and Dohme and Novartis. Investigators supported by Prostate Cancer Foundation (PCF) and National Health and Medical Research Council (NHRMC).DisclosureM.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). 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. A.A. Hamid: Financial Interests, Personal, Advisory Board, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Institutional, Local PI: Astellas. P.H. Kuo: Financial Interests, Institutional, Research Grant, Research Grant and Speaker: Blue Earth Diagnostics, General Electric Healthcare; Non-Financial Interests, Institutional, Invited Speaker: Attralus, Chimerix, Eli Lilly, Fusion Pharma, Invicro, Life Molecular Imaging, Navidea, Novartis, Radionetics, Telix Pharmaceuticals; Non-Financial Interests, Institutional, Advisory Board, Advisory Board and Speaker: dGenThera. D.L. Chen: Financial Interests, Personal, Invited Speaker, Invited speaker for educational symposia at SNMMI and RSNA Annual Meetings: GE Healthcare; Financial Interests, Personal, Royalties, Co-inventor on WO 2015103526 A1: Mach RH, Chu W, Zhou D, Michel LS, Chen DL. Radiolabeled tracers for poly(adp-ribose)polymerase-1 (PARP-1), methods and uses therfor. Patent held by Washington University in St. Louis and licensed to Trevarx: Washington University and Trevarx; Financial Interests, Institutional, Funding, In-kind funding support for clinical trial: Telix Pharmaceuticals; Financial Interests, Institutional, Research Grant, Research funding for PET/MR imaging: United Imaging; Non-Financial Interests, Leadership Role, President of Center for Molecular Imaging Innovation and Translation: SNMMI; Non-Financial Interests, Other, Member, Nuclear Medicine Review Committee: ACGME. A.J. Armstrong: Financial Interests, Personal, Other, Consultant: Astellas; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Merck, Bayer, Janssen, Myovant, Telix, Z Alpha; Financial Interests, Institutional, Coordinating PI: Pfizer, Janssen, BMS, Bayer, Astellas, Pathos; Financial Interests, Institutional, Local PI: Merck, Amgen; Financial Interests, Institutional, Steering Committee Member: AstraZeneca. 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 dont receive any compensation for this.: Novartis; Non-Financial Interests, Principal Investigator, I am the Priincipal 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. M.J. Morris: Financial Interests, Personal, Advisory Board: Oric, Pfizer, Exelixis, Lantheus, AstraZeneca, Amgen, Daiichi Sankyo, Convergent, Clarity Pharmaceuticals, Blue Earth Diagnostics, POINT Biopharma, Telix, Z-alpha; Financial Interests, Personal, Invited Speaker: Progenics, ITM Isotope Technologies; Financial Interests, Personal, Stocks/Shares: Doximity; Financial Interests, Institutional, Coordinating PI: Novartis, Celgen; Financial Interests, Institutional, Local PI: Corcept, Janssen, Astellas; Non-Financial Interests, Advisory Role: Bayer, Janssen Oncology, Novartis; Other, Travel to conference: AstraZeneca; Other, Travel/lodging at conference: APCCC. All other authors have declared no conflicts of interest.