1809P - Dynamics of plasma tumour DNA and copy number alterations in advanced metastatic castration-resistant prostate cancer (mCRPC) patients treated with cabazitaxel: A prospective biomarker trial

Background

Liquid biopsies enable non-invasive detection of circulating biomarkers for disease monitoring and treatment resistance interrogation. We aimed to study circulating tumour DNA (ctDNA) to identify biomarkers of response from cabazitaxel in mCRPC patients (pts).

Methods

mCRPC pts (N=104) candidate for cabazitaxel treatment were enrolled in a prospective biomarker multi-centre trial (NCT03381326). Plasma was collected at baseline (BL), prior to cycle 3/4 (C3) and at progression (PD) and analyzed using a bespoke prostate cancer capture panel (PCF_SELECT, Orlando et al, NAR Cancer 2022 ). ctDNA fraction was calculated using allelic imbalance-based quantitation of the most abundant hemi-deletions. Primary outcome measures were overall survival (OS) and progression-free survival (PFS). Medians and [IQR] or 95% CI are reported.

Results

97 pts were evaluable. ctDNA fraction was significantly lower at C3 (0.05 [0.04-0.38]) versus (vs) BL (0.40 [0.25-0.51]) and PD (0.41 [0.27-0.59] p=0.003). ctDNA dynamics strongly associated with outcome: pts with any increase in ctDNA fraction at C3 vs BL (N=20/65) had the worst outcome (PFS 2.6 months (mo), 95% CI 2.2-3.1; OS 7.5 mo, 95% CI 5.2-9.9) whilst pts who had a decrease at C3 (N=27/65) had a similar PFS (6.7 mo, 95% CI (5.1-8.2) but worse OS (15.7 mo, 95% CI 11.4-21.4) compared to undetectable ctDNA at both BL and C3 (N=18/65; PFS 8.2 mo, 95% CI 4.9-11.2; OS 29.9 mo, 95% CI 22.5-39.6). Median ctDNA fraction was significantly higher (0.50 [0.38-0.64]) in early progressors (at or before C3) vs late (after 4 cycles; 0.32 [0.17-0.55] p=0.03). In samples with detectable ctDNA, there was overall a consistent prevalence of gene copy number alterations at BL and PD; however, a significantly higher prevalence of gains of PIK3CB (chr3q22; 55 vs 29%, p=0.01) and AKT1 (chr14q32; 31 vs 14%, p=0.048) was observed in PD samples compared to BL.

Conclusions

ctDNA dynamics associated with cabazitaxel outcomes and identified pts progressing early. An enrichment in PIK3CB and AKT1 gains was observed upon cabazitaxel progression.

Clinical trial identification

NCT03381326.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Sanofi Genzyme.

Disclosure

N. Brighi: Financial Interests, Personal, Other, Travel grant: Ipsen, Novartis, Janssen Cilag, Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: BMS. G. Gurioli: Financial Interests, Personal, Other, Travel grant: Sanofi. V. Conteduca: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Merck, AstraZeneca, Amgen, Eisai, Recordati, Bayer; Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas, Janssen, Ipsen, Bayer, Gilead, BMS. C. Lolli: Financial Interests, Personal, Speaker, Consultant, Advisor: Ipsen, BMS, MSD. E.F. Giunta: Financial Interests, Personal, Other, Travel grant: Janssen Cilag. U. Basso: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Invited Speaker: Ipsen, Janssen, Astellas, AstraZeneca, MSD, Merck; Financial Interests, Institutional, Funding, Research Grants: Ipsen. F. Pierantoni: Financial Interests, Personal, Other, Travel expenses: Pfizer, MSD, BMS, AstraZeneca, JNJ, Merck, Takeda; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, JNJ, MSD, Takeda; Financial Interests, Personal, Advisory Board: Lilly. G. Fornarini: Financial Interests, Personal, Advisory Board: Amgen, Astellas, BMS, Janssen, Eisai, Ipsen, Pfizer, Bayer; Financial Interests, Personal, Other, ESMO meeting - travel accommodation: Ipsen. G.L. Banna: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Astellas; Financial Interests, Personal, Other, Travel grants: Janssen. F. Demichelis: Financial Interests, Personal, Royalties, Coinventor on a patent for Gene Fusion Prostate Cancer (Harvard/Michigan) in the area of diagnostics and therapeutics: The University of Michigan and The Brigham and Women’s Hospital. U.F.F. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, Eisai, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Clovis Oncology, AstraZeneca; Financial Interests, Institutional, Research Grant: AstraZeneca, Sanofi, Roche. G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca; Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion, Novartis; Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research; Financial Interests, Institutional, Advisory Board: Artera, Veracyte; Financial Interests, Institutional, Research Grant: Janssen, Astellas, Novartis; Financial Interests, Institutional, Coordinating PI: Janssen; Financial Interests, Institutional, Local PI: Novartis, Pfizer; Non-Financial Interests, Principal Investigator: Janssen, Astellas; Non-Financial Interests, Advisory Role: Janssen, AstraZeneca; Non-Financial Interests, Project Lead: Artera, Veracyte. All other authors have declared no conflicts of interest.