1812P - Exploration of germline (g) vs somatic (s) origin of homologous recombination repair (HRR) gene alterations and potential associations with antitumor activity in the HRR-deficient population from TALAPRO-2

Background

TALAPRO-2 evaluated the PARP inhibitor talazoparib (TALA) combined with the androgen receptor pathway inhibitor enzalutamide (ENZA) as 1st-line treatment in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint was radiographic PFS (rPFS) assessed centrally. Exploratory biomarker analyses assessed g vs s origin of HRR gene alterations and potential associations with efficacy in the HRR-deficient population from TALAPRO-2.

Methods

Alterations were defined as known/likely pathogenic variants. The frequency of gHRR alterations (gHRRm) was assessed in pts evaluable for saliva sequencing using the Ambry CustomNext-Cancer panel (sequenced 9/12 genes from the HRR12 tumor panel). Association of g vs s tumor HRRm and efficacy was assessed in the ITT population using saliva data (or solid tumor s-g-zygosity prediction when adequate saliva results unavailable) to annotate tumor alteration origin (limited to short variants). Associations with rPFS were evaluated using a stratified log-rank test. Data cutoff: October 3, 2022.

Results

91/302 pts (30.1%) evaluable for gHRR exhibited ≥1 HRR alteration in their saliva: BRCA2 (14.9%); CHEK2 (7.3%); ATM (4.0%); PALB2 (2.3%); BRCA1 (1.0%); NBN (1.0%); MRE11A (0.7%); MLH1 (0.3%). Where evaluable, solid tumor and prospectively tested baseline ctDNA HRR alterations were typically of s origin (eg BRCA2 [44 g vs 50 s], CDK12 [1 g vs 27 s], ATM [14 g vs 49 s]) with some exceptions (eg BRCA1 [7 g vs 4 s], CHEK2 [24 g vs 2 s], NBN [5 g vs 2 s]). rPFS was comparable for pts with g and s alterations in the TALA + ENZA arm (HR 0.74, 95% CI, 0.35–1.58; 2-sided P value = 0.44), but relatively shorter for gHRRm pts in the placebo (PBO) + ENZA arm (HR 1.87, 95% CI, 1.06–3.30; P = 0.03).

Conclusions

GHRRm incidence in mCRPC pts with tumor HRRm was 30.1%. No association with differential antitumor activity for TALA + ENZA was observed in tumors bearing HRRm of g vs s origin. Though the analyses were exploratory, a shorter rPFS in PBO + ENZA-treated gHRRm pts may reflect an intrinsically poor prognosis subgroup that could be prioritized for TALA + ENZA treatment. Further study is warranted.

Clinical trial identification

NCT03395197.

Editorial acknowledgement

Editorial support was provided by Ellen Woon, PhD, 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

This study was funded by Pfizer Inc. Astellas provided enzalutamide.

Disclosure

S.M. Yip: Financial Interests, Personal, Speaker, Consultant, Advisor: Amgen, Astellas, AstraZeneca, Merck, Bayer, BMS, Novartis, Pfizer, Hoffman-La Roche, Ipsen, Janssen, and OncoHelix. 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. N. Matsubara: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Coordinating PI: Janssen, Roche, MSD, Taiho, Pfizer, Chugai; Financial Interests, Institutional, Local PI: AstraZeneca, Bayer, Astellas, Amgen, Eisai, Eli Lilly, AbbVie. A.A. Azad: Financial Interests, Personal, Advisory Board: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono, Janssen, BMS, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dohme; Financial Interests, Personal, Other, Consultant: Aculeus Therapeutics; Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Novartis, Amgen, Ipsen, BMS, Merck Serono, Bayer; Financial Interests, Personal, Other, Travel + Accommodation: Astellas, Merck Serono, Amgen, Novartis, Janssen, Tolmar, Pfizer, Bayer; Financial Interests, Personal, Research Grant: Astellas, Merck Serono, AstraZeneca; Financial Interests, Personal, Steering Committee Member: Astellas, Pfizer, Exelixis; Financial Interests, Institutional, Local PI: BMS, Aptevo Therapeutics, AstraZeneca, GSK, Pfizer, Astellas, SYNthorx, Bionomics, Sanofi, Ipsen, Exelixis, Merck Sharpe Dohme, Janssen, Eli Lilly, Gilead Sciences, Merck Serono, Hinova; Financial Interests, Institutional, Trial Chair: Bayer; Financial Interests, Institutional, Coordinating PI: AstraZeneca, Hinova; Non-Financial Interests, Leadership Role, Chair, Translational Research Committee: ANZUP Cancer Trials Group; Non-Financial Interests, Leadership Role, Member, Scientific Advisory Committee: ANZUP Cancer Trials Group; Non-Financial Interests, Leadership Role, Chair, Urologic Oncology Committee: Clinical Oncology Society of Australia; Non-Financial Interests, Other, Editorial Board Member: BMC Urology; Non-Financial Interests, Other, Associate Editor: Cancer Research Communications, Frontiers in Oncology. P.C. Fong: Financial Interests, Personal, Speaker, Consultant, Advisor: MSD; Financial Interests, Personal, Other, travel, accommodations, and/or expenses: Pfizer. J. Carles Galceran: Financial Interests, Personal, Advisory Board: Astellas Pharma, AstraZeneca, Bayer, Johnson & Johnson, MSD Oncology, Novartis (AAA), Roche, Sanofi; Financial Interests, Institutional, Local PI: Janssen Cilag International NV, Lilly, S.A, Medimmune, Novartis Farmacéutica, S.A, Sanofi-Aventis, S.A; Other, Other, Member of the Comission: Catalan Program of Ambulatory Medication Comission (CAHMDA). 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. R.J. Jones: Financial Interests, Personal, Other, Honoraria: Astellas Pharma, Bayer, BMS, Ipsen, Janssen, Merck Serono, MSD, Pfizer, and Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas Pharma, Bayer, BMS, Ipsen, Janssen, Merck Serono, MSD, Novartis, Pfizer, and Roche; Financial Interests, Personal, Research Funding: Astellas Pharma, Bayer, Clovis Oncology, Exelixis, and Roche; Financial Interests, Personal, Other, travel, accommodations, and/or expenses: Bayer and Janssen. A.P. Fay: Financial Interests, Personal, Other, Honoraria: Astellas Pharma, AstraZeneca, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; Financial Interests, Personal, Speaker, Consultant, Advisor: Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; Financial Interests, Personal, Stocks or ownership: Brazilian Information Oncology; Financial Interests, Personal, Research Funding: AstraZeneca, BMS, CAPES – CNPq, Foundation Medicine, Ipsen, MSD, and Roche; Financial Interests, Personal, Other, travel, accommodations and/or expenses: Astellas Pharma, AstraZeneca, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche. S. Zschäbitz: Financial Interests, Personal and Institutional, Speaker, Consultant, Advisor: Amgen, Bayer; Financial Interests, Personal, Speaker, Consultant, Advisor: Eisai, Novartis, Janssen; Financial Interests, Institutional, Speaker, Consultant, Advisor: BMS, MSD, and Pfizer; Financial Interests, Personal and Institutional, Advisory Board: Amgen, Bayer; Financial Interests, Personal, Advisory Board: Eisai, Janssen, Novartis; Financial Interests, Institutional, Advisory Board: BMS, MSD, and Pfizer. J. Oldenburg: Financial Interests, Personal, Advisory Board: BMS, MSD, Pfizer, Roche, Astellas, AstraZeneca, Bayer, Eisai, Ipsen, Janssen-Cilaq; Financial Interests, Institutional, Coordinating PI: BMS, MSD, Sanofi; Financial Interests, Institutional, Local PI: BMS. N. Di Santo, C.G. Healy, X. Lin, D. Laird: Financial Interests, Personal, Stocks or ownership: Pfizer; Financial Interests, Personal, Full or part-time Employment: Pfizer. N. Agarwal: Financial Interests, Personal, Advisory Board, In the last two calendar years, I participated in the scientific advisory board of these pharma companies between February 2021 to April 2021. None after that: Merck, Aveo, Gilead, Lilly, Exelixis, Foundation Medicine; Financial Interests, Trial Chair, I am involved in the following phase 3 trials as the trial co-chair: TALAPRO-2, TALAPRO-3 (both Pfizer), and CONTACT-2 (Exelxis): Pfizer, Exelixis; 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, BMS, 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, and 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, Clovis, Crispr, Eisai, Eli Lilly, Exelixis, Immunomedics, Janssen; 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, and Tracon. All other authors have declared no conflicts of interest.