1616P - Circulating tumour DNA (ctDNA) measurements and PET-imaging to evaluate response in a phase Ib trial of metastatic castration-resistant prostate cancer (mCRPC) treated with Lutetium-177-PSMA-617 (LuPSMA) plus pembrolizumab (PRINCE)

Background

The PRINCE trial showed promising activity for LuPSMA in combination with pembrolizumab, an anti-programmed death 1 inhibitor. Here, we present an exploratory analysis of serial ctDNA measurements and PSMA-PET imaging to identify predictors of response to LuPSMA plus pembrolizumab.

Methods

We analyzed plasma ctDNA and PSMA-PET imaging for patients enrolled in the PRINCE trial at baseline (n=37) and after 12 weeks of treatment (n=35). Patients also underwent FDG-PET at baseline. Targeted sequencing of plasma and matched white blood cell DNA was used to estimate ctDNA fractions (ctDNA%). We associated ctDNA% at baseline (undetected, 1-30%, and >30%) and after 12 weeks (undetected vs detected), baseline PSMA-SUVmean (<10 and ≥10), and total tumor volume (TTV) on PET-imaging with PSA90 response rate (RR) and radiographic PFS (rPFS).

Results

Baseline ctDNA% was moderately correlated with FDG metabolic tumor volume (rho=0.47, p<0.01) and PSMA TTV (rho=0.53, p<0.01). PSMA-SUVmean<10 (21/37 patients) was associated with a higher ctDNA% compared to PSMA-SUVmean≥10 (median 30% vs 4%, p=0.03). Baseline ctDNA<30% (HR 0.4, 95%CI 0.2-0.8) and PSMA-SUVmean≥10 (HR 0.3, 95%CI 0.1-0.7) showed superior rPFS. Patients with both ctDNA<30% and PSMA-SUVmean≥10 had the longest rPFS (n=12; median not-reached). In contrast, the median rPFS was similar for all patients with either ctDNA>30% (n=4; 8.0 months), PSMA-SUVmean<10 (n=11; 4.6 months) or both (n=10; 6.0 months). PSA90 RR was higher in patients with undetected ctDNA by 12 weeks (16/17; 94%) compared to patients with persistent ctDNA at 12 weeks (1/18; 6%). Patients with persistent ctDNA detection at 12 weeks also had worse rPFS (HR 6.3, 95% CI 2.5-15.7).

Conclusions

Both PSMA SUVmean and baseline ctDNA% demonstrate prognostic potential for rPFS. Combining both parameters warrant further investigation to determine their additive or complementary roles in enhancing prognostic accuracy. Early on-treatment ctDNA% measurements may help further stratify the depth and durability of response.

Clinical trial identification

NCT03658447.

Editorial acknowledgement

Legal entity responsible for the study

Shahneen Sandhu.

Funding

This study was funded by Merck Sharpe and Dohme and Novartis.

Disclosure

S.H. Tolmeijer: Financial Interests, Personal, Invited Speaker: Bayer. E.M. Kwan: Financial Interests, Personal, Advisory Role: Astellas Pharma, Janssen, Ipsen; Financial Interests, Personal, Other: Astellas Pharma, Pfizer, Ipsen, Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Ipsen, Astellas Pharma, Research Review; Financial Interests, Institutional, Research Funding: Astellas Pharma, AstraZeneca. A. Joshua: Financial Interests, Institutional, Advisory Role: Janssen Oncology, Ipsen, AstraZeneca, Sanofi, Pfizer, Novartis, Merck Serono, Eisai, IDEAYA Biosciences, IQVIA, Bayer, Astellas Pharma, Grey Wolf Therapeutics, Medison, Starpharma; Financial Interests, Personal, Royalties: Cancer therapeutic methods; Financial Interests, Personal, Stocks or ownership: Pricilium Therapeutics, Opthea; Financial Interests, Institutional, Research Funding: Bristol Myers Squibb, Janssen Oncology, Merck Sharp & Dohme, Mayne Pharma, Roche/Genentech, Bayer, Lilly, Pfizer, AstraZeneca, Corvus Pharmaceuticals, Lilly. 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. M. Crumbaker: Non-Financial Interests, Advisory Role, 1 off advisory board meeting - March 2023: Astellas. A. Anton: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Bayer, MSD; Financial Interests, Institutional, Research Funding: Mundipharma, Astellas, AstraZeneca, Amgen, Janssen, MSD, Bayer. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Institutional, Invited Speaker: Astellas, Janssen, Amgen; Financial Interests, Institutional, Advisory Board: Astellas, Bayer; Financial Interests, Institutional, Invited Speaker, Bayer paid for travel to Lisbon APEX meeting and accommodation. I gave 3 talks and honorarium paid to be institution: Bayer; Financial Interests, Personal, Member of Board of Directors, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Full or part-time Employment, I am a medical oncologist, Director of Research and Chief Clinical Officer of this cancer centre: Chris O'Brien Lifehouse; Financial Interests, Personal, Full or part-time Employment, I am a member of the Garvan Faculty and Laboratory Head: Garvan Institute of Medical Research; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Other, I am inventor of a patent lead by my institution above: International (PCT) Patent Application No. PCT/AU2023/050849Prognostic Markers (plasma lipid prognostic signature in metastatic prostate cancer). Inventors: Horvath L, Meikle P, Scheinberg S, Lin HM, Sullivan D: Chris O'Brien Lifehouse; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Local PI, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Local PI, AMG160 Phase 1AMG509 Phase 1AMG757 Phase 1: Amgen; Financial Interests, Institutional, Local PI, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Local PI, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Local PI, TALAPRO2, TALAPRO3: Pfizer; Financial Interests, Institutional, Local PI, CYCLONE-2, CYCLONE-3: Eli Lilly; Financial Interests, Institutional, Steering Committee Member, ENZAMET, ENZARAD, DASL-HiCAP, GUIDE, ANZAdapt: ANZUP; Financial Interests, Institutional, Local PI, GALAHADACISPrevalence: Janssen-Cilag; Financial Interests, Institutional, Local PI, GSK204697: GSK; Financial Interests, Institutional, Local PI, XL184-021: Exelexis; Financial Interests, Institutional, Local PI, BGB-A317BGB-283BGB-A317-290: BeiGene; Financial Interests, Institutional, Local PI, FPT155-001: Five Prime; Financial Interests, Institutional, Local PI, AB928CSP0003: ARCUS; Financial Interests, Institutional, Local PI, ATG-017 and ATG-019: Antagene; Financial Interests, Institutional, Local PI, JANUX007: Janux; Financial Interests, Institutional, Local PI, Petranha: Astrazeneca; Financial Interests, Institutional, Local PI, ENZAMET, ENZA-P, Upfront PSMA, ANZAdapt, GUIDE: ANZUP; Financial Interests, Institutional, Local PI, HP-518-CS-001: Hinova; Financial Interests, Institutional, Local PI, JANX007: Janux Therapeutics; Non-Financial Interests, Leadership Role, Professor of Medical Oncology (Genitourinary cancer): University of Sydney; Non-Financial Interests, Leadership Role, Adjunct Professor: University of New South Wales. M.S. Hofman: Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker, PROSPECT23: Janssen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Research Grant: Novartis, Isotopia Molecular Imaging, Bayer; Other, Research Support: Prostate Cancer Foundation (PCF). A.W. Wyatt: Financial Interests, Personal, Speaker, Consultant, Advisor: Janssen, Astellas Pharma, AstraZeneca, Merck, Bayer, Pfizer, EMD Serono; Financial Interests, Institutional, Research Funding: ESSA, Tyra Biosciences. 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 don’t 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 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. All other authors have declared no conflicts of interest.