1613P - Clinically advanced prostate cancer (CAPC) featuring BRCA2 loss: A comprehensive genomic profiling (CGP) study

Background

CAPC with BRCA2 loss may experience prolonged benefit with PARP inhibitors (PARPi) due to the inability of these tumors to acquire BRCA2 reversion mutations. Biomarker and genomic alteration (GA) findings in BRCA2-loss CAPC were compared with BRCA2 wild type (wt) and BRCA2 short variant mutated (svmut) CAPC.

Methods

21,821 stages III and IV CAPC underwent hybrid capture based CGP (CGP) to evaluate all classes of GA, MSI status, TMB, homologous recombination score (HRD), genomic ancestry and signature. 569 CAPC had BRCA2-loss, 1,071 had BRCA-svmut and 20,181 had BRCAwt. PD-L1 expression was tested by IHC.

Results

Both BRCA2-loss and BRCA2-svmut CAPC had more frequent GA per tumor than BRCA2wt CAPC (P<.0001 for both comparisons). No differences in the ages and genomic ancestry in all three CAPC groups including AFR ancestry which ranged from 14.4% to 15.4%. BRCA2-loss CAPC had higher TMPRSS2-ERG fusions than BRCA2-svmut (36.6% v 22.8%; P<.0001) and BRCA2wt (36.6% v 22.8%; P<.0001) and lower SPOP GA than BRCA2wt (7.9% v 10.8%; p=.047) and lower CDK12 GA than BRCA2-svmut (0.2% v 2.4%; P=.001) or BRCA2wt 0.2% v 5.4%; P<.0001). BRCA2-loss CAPC had lower PTEN GA than BRCA2wt CAPC (26.5% v 31.8%; P=.015). Both BRCA2-loss and BRCA2-svmut CAPC had more RB1 GA than BRCA2wt (7.7% v 4.6%; P=.0003) potentially indicating neuroendocrine features. ATM mut were more frequent in BRCA2wt than either BRCA2-loss and BRCA2-svmut (P<.0001). BRCA2-svmut CAPC had more MSI high and TMB ≥10 mutations/Mb tumors (7.8% and 13.1%) than the BRCA2-loss (0.2% and 2.1%) or BRCA2wt (2.8% and 3.9%) groups (P<.0001 for all comparisons). CAPC with MMR signature were more frequent in BRCA2-loss and BRCA2svmut v BRCA2wt (P<.0001 for both comparisons). Low level (1-49% TPS) PD-L1 expression was similar in all 3 groups.

Conclusions

BRCA2-loss CAPC differs from both BRCA2-svmut and BRCA2wt CAPC across several biomarkers and genomic alteration levels, but not in certain clinical parameters, such as patient age and ancestry. Elucidation of the concurrent genomic landscape in BRCA2-altered CAPC may guide the development of future PARPi-based combination regimens to be further evaluated in relevant clinical trials.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

N. Agarwal: Financial Interests, Personal, Invited Speaker, Invited speaker: Medscape; Financial Interests, Personal, Invited Speaker, Invited Speaker: Onclive, Research to Practice, Clinical Care Options; Financial Interests, Institutional, Other, I serve in the leadership of my cancer center (Huntsman Cancer Institute, University of Utah. Salt Lake City, UT, USA). There are multiple research projects sponsored by these companies which pay money to my institution: Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, CRISPR, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, GSK, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, Telix, Tracon; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharmas with no personal honorarium.: AstraZeneca, Calithera, CRISPR, Eli Lilly, Exelixis, Immunomedics, Merck, Pfizer; Financial Interests, Steering Committee Member, I am involved in the steering committee of the trials sponsored by these pharma companies with no personal honorarium: Merck, Nektar, New Link Genetics, Oric, Pfizer, Prometheus, Rexahn, Takeda, Telix,Tracon; Financial Interests, Trial Chair, One of the two co-chairs of the clinical trials sponsored by these pharma companies. I have not received any honorarium for these roles: Pfizer, Exelixis, Janssen, Telix; Non-Financial Interests, Member, I am a long-standing member of ASCO and a volunteer. I was awarded the fellow of ASCO in 2023. I also act as the editor of the ASCO Daily News as a volunteer: Amercian Society of Clinical Oncology; Non-Financial Interests, Member, I am a member of this NCI and NCTN-sponsored cooperative clinical trial network group.: SWOG; Non-Financial Interests, Member, I am a member of these professional organizations.: AACR, AUA, PCF. S. Gupta: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Merck, Bayer, Pfizer, EMD Serono, Seattle Genetics, Gilead, Fuondation Medicine, Gaurdant, Astellas; Financial Interests, Personal, Speaker’s Bureau: Seattle Genetics, BMS, Gilead Science. P. Grivas: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD, Roche, BMS, AstraZeneca, Seagen, EMDSerono, Pfizer, Johnson & Johnson, Roche, Astellas, Gilead, Fresenius Kabi, Strata Oncology, AbbVie; Financial Interests, Institutional, Research Funding: Acrivon Therapeutics, MSD, ALX Oncology, BMS, Genentech, Gilead, EMD Serono, QED Therapeutics. R. Li: Financial Interests, Institutional, Research Funding: Veracyte, CG Oncology, Merck, Valar Labs, Predicine; Financial Interests, Personal, Other, Clinical trial protocol committee: CG Oncology, Johnson & Johnson, Merck; Financial Interests, Personal, Advisory Role: BMS, Arquer Diagnostics, Fergene, Merck, Urogen Pharma, Lucence, CG Oncology, Johnson & Johnson, Thericon; Financial Interests, Personal, Other, Honoraria: SAI MedPartners, Putnam Associates, Solstice Health Communications, Urotoday. D.C. Pavlick, R. P. Graf: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine. J.S. Ross: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Ownership Interest: Roche Holdings, Celsius therapeutics, Tango Therapeutics. A. Necchi: Financial Interests, Institutional, Advisory Role: MSD, Roche, Bayer, AstraZeneca, Astellas, Johnson & Johnson, Incyte, BMS, Clovis Oncology, GSK, Bycicle Therapeutics, Catalym, Basilea Pharmaceutica; Financial Interests, Institutional, Research Funding: AstraZeneca, Ipsen, Gilead, MSD; Financial Interests, Personal and Institutional, Other, Travel, Accommodations, Expenses: Roche, MSD, AstraZeneca, Johnson & Johnson, Pfizer, Rainer Therapeutics; Non-Financial Interests, Personal, Stocks or ownership, Spouse: Bayer. All other authors have declared no conflicts of interest.