1612P - Impact of FANCA, ATM, CDK12 alterations on survival in metastatic castration-resistant prostate cancer (mCRPC)

Background

Alterations (alt) in non-BRCA homologous recombination repair (HRR) genes represent a heterogeneous group that may impact the outcome of mCRPC patients (pts) but the clinical significance of each individual gene is poorly understood. We investigated the impact of individual non-BRCA HRR alt on the outcome of mCRPC pts treated on 1L with an androgen receptor pathway inhibitor (ARPI) or a taxane.

Methods

Eligible pts included in the CAPTURE study from PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620), and PROSABI (NCT02787837) studies underwent paired somatic/germline DNA analyses using a custom NGS panel that included ATM, BRCA1, BRCA2, BRIP1, CDK12, CHEK2, FANCA, HDAC2, PALB2, RAD51B, and RAD54L. Pts were classified as non-BRCA HRR (ATM, FANCA, CDK12, other genes) if pathogenic (likely) alt in ≥1 allele & no concomitant BRCA alt present. rPFS and OS were reported for BRCA, non-BRCA HRR and non-HRR subgroups; association with outcome was assessed using multivariable Cox-regression models including baseline variables with known prognostic value. Hazard ratios (HR) with 95% confidence intervals (CIs) and p values are presented.

Results

Of 729 pts, 223 (30.6%) had alt in HRR genes, including 96 (13.2%) BRCA, 52 (7.3%) ATM, 26 (3.2%) FANCA, 14 (2%) CDK12 and 34 (4.8%) pts with other non-BRCA HRR alt. 1 pt with co-occurring FANCA + CDK12 mutation was excluded. After adjusting for baseline covariates, ATM alt were associated with better OS compared with BRCA alt. Pts with FANCA alt showed no difference when compared to pts with BRCA alt. Both pts with FANCA and CDK12 alt had a significantly worse OS than those without HRR alt (Table). CIs are relatively wide due to small number of pts. Table: 1612P

Conclusions

FANCA, ATM and CDK12 alt are associated with different outcomes. The marked heterogeneity in prognostic significance may not justify pooling non-BRCA HRR alt as a single entity. Further studies are needed to elucidate the clinical significance of each alt independently.

Clinical trial identification

PROREPAIR-B (NCT03075735), PROSENZA (NCT02922218), PROSTAC (NCT02362620), PROSABI (NCT02787837).

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Janssen.

Disclosure

D. Lorente: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, Bayer, Sanofi, Bristol Myers Squibb, AstraZeneca, MSD; Financial Interests, Personal, Advisory Board: Janssen, Sanofi, Pfizer, AstraZeneca; Financial Interests, Personal, Other, Travel: Bayer, Pfizer. B. Herrera Imbroda: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Astellas, Bayer; Financial Interests, Personal, Invited Speaker: Ipsen. N. Romero Laorden: Financial Interests, Personal, Advisory Role: AstraZeneca, Clovis Oncology, GSK, Janssen, MSD; Financial Interests, Institutional, Research Funding: Janssen-Cilag, MSD, Pfizer. M.J. Mendez Vidal: Financial Interests, Personal, Advisory Board: BMS, MSD, Novartis, Ipsen, Astellas, Pfizer, Merck, Sanofi, Eisai, Bayer; Financial Interests, Personal, Invited Speaker: BMS, Ipsen, Roche, Astellas, Merck, Bayer; Non-Financial Interests, Other, Travel expenses: Ipsen, BMS. C. Capone, A.M. Vanden Broecke, M. Trevisan, S. Van Sanden, A. Jürgens: Financial Interests, Personal, Full or part-time Employment: Janssen. E. Gonzalez Billalabeitia: Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Bayer; Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer; Financial Interests, Personal, Other, Travel Grant: Pfizer, Janssen; Financial Interests, Institutional, Coordinating PI, IIS Phase 2 Pembrolizumab in combination with Carboplatin and Cabazitaxel in AVPC: MSD; Financial Interests, Institutional, Research Grant, Translational research project in PTEN defective prostate cancer: AstraZeneca; Financial Interests, Institutional, Research Grant, Translational research grant for biomarkers associated with a clinical trial.: Janssen. D. Olmos: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Clovis Oncology, Daiichi Sankyo, Janssen, MSD Oncology; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Bayer, Janssen, Pfizer, MSD; Financial Interests, Institutional, Research Funding: AstraZeneca, Bayer, Genentech/Roche, Janssen, MSD Oncology, Pfizer. E. Castro: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen, MSD, Bayer, Pfizer, Daiichi Sankyo, Lilly, Medscape, Novartis; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, Clovis, Pfizer, Medscaoe; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Janssen, Bayer, Pfizer; Financial Interests, Institutional, Local PI: Janssen, Pfizer, MSD. All other authors have declared no conflicts of interest.