1825P - Molecular features of circulating tumour cells (CTCs) associate with response to 177Lu-PSMA-617 plus pembrolizumab for metastatic castration resistant prostate cancer (mCRPC)

Background

The phase I PRINCE trial (NCT03658447) is evaluating efficacy of ¹⁷⁷Lu-PSMA-617 plus pembrolizumab for mCRPC. Genomic and clinical features at baseline of patients who respond best to this combination are not yet known.

Methods

A total of 37 patients were enrolled. PSA levels were assessed 3 weekly. CTCs (CK+, CD45-, and DAPI+) were enumerated from 3ml of blood, immunoassayed for Prostate Specific Membrane Antigen (PSMA) expression, and single CTCs profiled with low-pass whole-genome sequencing (Epic Sciences). Baseline PSMA-PET metabolic tumour volume (MTV) and PSMA expression (SUV) were measured. Patients were split into response groups based on the best percentage change in PSA from baseline: Good (drop in PSA >90%, n=17), Intermediate (drop in PSA <90%, n=16) and Poor (no decrease in PSA, n=4). Wilcoxon and Kruskal-Wallis tests were used for pairwise and multi-group comparisons, respectively.

Results

MTV (mls) was lower in the Good (median: 218) than in both Intermediate (median: 328) and Poor (median: 538) response groups, but pairwise comparison of Good versus Intermediate-Poor responders combined was not significant (Wilcoxon p=0.286). The strongest image-based association was mean PSMA-PET SUV, which increased from Poor (median: 7.8), to Intermediate (median: 8.5) and Good (median: 11) responders, achieving a Wilcoxon p-value of 0.079 for the Good versus the Intermediate-Poor groups. In contrast, stronger associations with PSA response were based on features of baseline CTCs. Baseline PSMA+ CTC counts were higher in Good (mean: 23.7) than Intermediate (mean: 4.3) and Poor (mean: 6) responders (p=0.022). Number of Large-scale State Transitions, a measure of genome instability was lowest for CTCs in Good (mean: 10.2), higher in Intermediate (mean: 15.1), and highest in Poor responders group (mean: 24.4), a highly significant trend (Kruskal-Wallis p=0.0004).

Conclusions

In the PRINCE cohort, CTCs data were more strongly associated with extent of drop in PSA than PET metrics.

Clinical trial identification

NCT03658447.

Editorial acknowledgement

Legal entity responsible for the study

Peter MacCallum Cancer Centre.

Funding

Epic Sciences Merck, Sharp and Dohme Novartis Victorian Cancer Agency.

Disclosure

S. Gupta, T. Singer, E. Lam, L. Fernandez, E. Jimenez, D. Zhang, Y. Lin, R.J. Wenstrup: Financial Interests, Personal and Institutional, Full or part-time Employment: Epic Sciences. 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. 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: BMS; 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 BMS sponsored studies and don't receive any renumeration for this: BMS; 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 BMS sponsored trial and I do not receive renumeration for this: BMS. All other authors have declared no conflicts of interest.