1815P - Emergent circulating tumor DNA (ctDNA) variants and ctDNA burden dynamics with potential associations with talazoparib antitumor activity in TALAPRO-1

Background

TALAPRO-1 evaluated talazoparib in patients (pts) with mCRPC and homologous recombination repair (HRR) alterations (11-gene panel, including BRCA1/2, PALB2, and ATM), who had received at least a taxane-based chemotherapy regimen and progressed on ≥1 novel hormonal therapy. Primary endpoint was objective response rate (RECIST 1.1) by blinded independent central review. Exploratory biomarker analyses assessed ctDNA and its associations with antitumor activity.

Methods

Serial ctDNA samples from Weeks (Wks) 1, 9, and 25, and Safety follow-up visit (SFUV) were assessed using FoundationOne Liquid CDx. Plasma tumor fraction (TF) was calculated based on tumor aneuploidy as described by Husain et al ( JCO Precis Oncol 2022; 6:e2200261). Data cut-off was September 4, 2020 (primary completion date).

Results

BRCA2 mutational complexity (variants/BRCA2m pts) was 18/16 (1.1), 12/10 (1.2), 62/11 (5.6), and 57/14 (4.1) at Wks 1, 9, and 25, and SFUV, respectively. At Wk 25, the median number of BRCA2 variants was 2 (range 1–18; 3 pts had ≥15 variants). Mutational complexity increased for BRCA1 and PALB2 by Wk 25 but remained unchanged for ATM. Of 26 evaluable pts, 7 cases of emergent variants in PARP1, PARP2, or PARP3 at Wk 25 and/or SFUV were detected. These included 5 cases of PARP1 variants predicted to truncate PARP1 and/or inhibit talazoparib binding, including 3 cases of A898T. 15/27 pts had TF quantifiable at Wk 1 (range 10−68%). Of these 15 pts, 10 had TF below limit of quantitation (BLQ; 10%), 1 had TF reduction ≥50%, and 4 had TF unchanged (change <50%) at Wk 9. Reductions to BLQ were seen in 4/4 with partial response, 2/2 with non-complete response/non-progressive disease, 3/5 with stable disease (an additional patient reduced ≥50%), and 1/4 with progressive disease.

Conclusions

Increased mutational complexity of genes in the BRCA1-PALB2-BRCA2 axis and emergent PARP variants likely reflects selective pressure to escape talazoparib-mediated synthetic lethality and/or PARP trapping. Early reductions in TF were evident and numerically more common in pts with antitumor responses. Further exploration of emergent variants in HRR and PARP genes and of ctDNA burden are warranted.

Clinical trial identification

NCT03148795.

Editorial acknowledgement

Editorial support was provided by Ama Edusei, PharmD, of CMC Affinity, a division of IPG Health Medical Communications.

Legal entity responsible for the study

Pfizer is responsible for the governance, coordination and running of the study.

Funding

Pfizer.

Disclosure

E. Castro: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen, MSD, Bayer, Pfizer; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, Clovis, Pfizer; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca, Pfizer; Financial Interests, Institutional, Research Grant: Janssen, Bayer; Financial Interests, Institutional, Local PI: Janssen, Pfizer. D. Laird: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks or ownership: Pfizer. T. Dorff: Financial Interests, Institutional, Advisory Board: Exelixis; Financial Interests, Personal, Other, drafted educational content (unbranded): Astellas; Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Sanofi. S. Zhao: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, EMD Serono, Exelixis, Janssen, Pfizer, Sanofi, and Seattle Genetics; Financial Interests, Personal, Research Funding: Pfizer. I.M. van Oort: Financial Interests, Personal, Speaker, Consultant, Advisor: AAA Novartis, Astellas Pharma, Bayer, Janssen, and MSD/AstraZeneca; Financial Interests, Personal, Research Funding: Astellas Pharma and Bayer. D. Gasparro: Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Janssen, Pfizer, and Sanofi. F. Calabro': Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, BMS, Ipsen, Merck, MSD, and Pfizer; Financial Interests, Institutional, Research Funding: AstraZeneca, Bayer, BMS, Eisai, Icon, Iqvia, J&J, Janssen, MSD, Parexel, Pfizer, PRA, Roche, and Syneos. S. Pignata: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, MSD, clovis, GSK, PharmaMar; Financial Interests, Institutional, Funding: Roche, MSD, Pfizer, AstraZeneca. L. Geczi: Financial Interests, Personal, Invited Speaker, Honoraria: BMS, Merck, and Pfizer. P. Barthelemy: Financial Interests, Personal, Advisory Board: BMS, MSD, Merck, Pfizer, Ipsen, Bayer, Janssen Cilag, Astellas, Novartis, Amgen, GILEAD; Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen. D. Kilari: Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Pfizer, Aveo oncology; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Institutional, Coordinating PI: Exelixis, Genentech; Financial Interests, Institutional, Local PI: Jounce. J.F. Hopkins: Financial Interests, Personal, Full or part-time Employment: Foundation Medicine; Financial Interests, Personal, Stocks or ownership: Roche Holding AG. H. Chen, C.G. Healy, J. Chelliserry: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks or ownership: Pfizer. G. Scagliotti: Financial Interests, Personal, Royalties: AstraZeneca, Eli Lilly, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, and Takeda; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, BeiGene, and Eli Lilly; Financial Interests, Institutional, Research Grant: Eli Lilly, MSD, and Tesaro; Financial Interests, Personal, Other, Travel & Accommodation: Bayer. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Menarini Silicon Biosystems, ImCheck Therapeutics, Crescendo; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics, Menarini Silicon Biosystems; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals, Crescendo, ImCheck Therapeutics; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. N. Mehra: Financial Interests, Personal, Advisory Board: Pfizer, Roche, MSD, AstraZeneca, Astellas, JNJ; Financial Interests, Institutional, Advisory Board: Janssen; Financial Interests, Institutional, Funding: Astellas, Pfizer; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Institutional, Coordinating PI: BMS, Janssen, BMS; Financial Interests, Institutional, Research Grant: AstraZeneca, BMS; Non-Financial Interests, Leadership Role, Head of the Prostate Cancer Working group: Dutch Uro-Oncology Study Group; Non-Financial Interests, Principal Investigator, co-PI: Prospective Bladder Cancer Infrastructure (Netherlands); Non-Financial Interests, Leadership Role: Castration-resistant Prostate Cancer Registry. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; Financial Interests, Personal, Advisory Board, February 2022: Arvinas; Financial Interests, Personal, Advisory Board, April 2022: Macrogenics; Financial Interests, Institutional, Research Grant, Trial chair: Pfizer, Bayer, AstraZeneca, Orion, MSD, BMS, Janssen; Non-Financial Interests, Principal Investigator, Chair of the 7DX phase 3 trial: BMS; Non-Financial Interests, Principal Investigator, Chair of the Docetaxel-pembrolizumab phase 3 trial: Merck; Non-Financial Interests, Principal Investigator, Chair of the Darolutamide BCR phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the PSMAfore phase 3 trial: AAA/Novartis; Non-Financial Interests, Principal Investigator, Chair of the CYPIDES ODM-208 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the STESIDES ODM-209 Phase I-II trial: Orion; Non-Financial Interests, Principal Investigator, Chair of the CAPITELLO 281 phase 3 trial: AstraZeneca; Non-Financial Interests, Principal Investigator, Chair of the TALAPRO-2 and TALAPRO-3 phase 3 trials: Pfizer; Non-Financial Interests, Principal Investigator, Chair of the RADIANT phase 3 trial: Bayer; Non-Financial Interests, Principal Investigator, Chair of the TRITON-3 phase 3 trial: Clovis.