1626P - Incidence of hematologic toxicities in the homologous recombination repair (HRR)-deficient population of the TALAPRO-2 trial and their potential association with germline vs somatic origin of HRR gene alterations

Background

TALAPRO-2 (NCT03395197) is a Phase 3 trial of talazoparib (TALA) + enzalutamide (ENZA) vs placebo (PBO) + ENZA in patients (pts) with metastatic castration-resistant prostate cancer (Fizazi et al. Nature Med 2024;30:257-264). In a previous analysis, radiographic progression-free survival was similar for pts with germline (g) and somatic (s) HRR gene alterations (HRRm) in the TALA + ENZA arm, but shorter for gHRRm vs sHRRm pts in the PBO + ENZA arm (Yip et al. Ann Oncol 2023;34(S2):1812P). Hematologic toxicities, especially anemia, are a class effect of poly(ADP-ribose) polymerase (PARP) inhibitors. We explore their incidence in the HRR-deficient population of TALAPRO-2 and possible associations with g vs s origin of HRRm.

Methods

In TALAPRO-2, pts were prospectively assessed for HRRm. Association analysis of gHRRm and sHRRm with hematologic toxicity was assessed within treatment arms (g vs s) and across treatment arms (g vs g and s vs s) using Fisher’s test.

Results

In the TALA + ENZA arm, any grade anemia was markedly less common in pts with gHRRm vs sHRRm; this was observed as well for neutropenia and thrombocytopenia (Table) but was not seen for grade ≥3 anemia (data not shown). In the PBO + ENZA arm, there was no marked difference in the observed incidence of hematologic toxicity in pts with gHRRm vs sHRRm. In pts with either gHRRm or sHRRm, there was a clinically meaningful higher incidence of any grade anemia (Table) in the TALA + ENZA arm vs the PBO + ENZA arm. In pts with sHRRm, any grade neutropenia and thrombocytopenia were more common in the TALA + ENZA arm than in the PBO + ENZA arm and there was a significant difference in overall hematologic toxicity.

Conclusions

Higher incidences of hematologic toxicities were observed in pts in the TALA + ENZA arm than in the PBO + ENZA arm, regardless of g or s origin of HRRm. However, hematologic toxicities were less pronounced in pts with gHRRm. Table: 1626P

Association between any grade hematologic toxicity and g vs s origin of HRRm

Clinical trial identification

NCT03395197.

Editorial acknowledgement

Medical writing support was provided by Annette Smith, PhD, on behalf of CMC Affinity, a division of IPG Health Medical Communications, and was funded by Pfizer.

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 Pharma, Inc. provided enzalutamide.

Disclosure

A.A. Azad: Financial Interests, Personal, Advisory Board: Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Telix, Merck Serono, Janssen, Bristol Myers Squibb, Ipsen, Bayer, Pfizer, Amgen, Noxopharm, Merck Sharpe Dohme, Daiichi Sankyo, Arvinas; Financial Interests, Personal, Other, Consultant: Aculeus Therapeutics; Financial Interests, Personal, Invited Speaker: Astellas, Janssen, Novartis, Amgen, Ipsen, Bristol Myers Squibb, 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: Bristol Myers Squibb, 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; Financial Interests, Personal, Trial Chair: Janssen, AstraZeneca; 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. 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. N.D. Shore: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Cold Genesys, Dendreon, Exact Imaging, Genesis Care Us, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Propella, Sanofi Genzyme, Speciality Networks, Tolmar, Urogen, Clarity, Lantheus, Lilly, Photocure, Telix, Photocure, Asieris, Alessa Therapeutics, Arquer, Fize medical, GConcology, Guardant, Ferring, Foundation Medicine, Immunitybio, Incyte, Minomic, NGM, Nonagen, Novartis, PlatformQ, Promaxo, Protara, Accord, Antev, Aura biosciences, Sumitomo; Financial Interests, Personal, Member of Board of Directors: Photocure, Alessa Theraputics; Financial Interests, Personal and Institutional, Local PI: AstraZeneca, Bayer, Aura, Exact Imaging, Janssen, Merck, Myovant, Novartis, Pfizer, Propella, Bristol Myers Squibb, Dendreon, Pfizer, Urogen; Financial Interests, Institutional, Local PI: alessa, GC oncology, FORMA therapeutics, Pacific edge, Point Biopharma, The MT group, Theralase, Verity, Astellas, Palette Life Sciences, Steba, Zenflow. J.C. 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, Member of the Comission: Catalan Program of Ambulatory Medication Comission (CAHMDA). A.P. Fay: Financial Interests, Personal, Other, Honoraria: Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, and Roche; Financial Interests, Personal, Advisory Role: Bayer, Ipsen, Janssen, MSD, Novartis, Pfizer and Roche; Financial Interests, Personal, Stocks or ownership: Brazilian Information Oncology; Financial Interests, Personal, Research Funding: AstraZeneca, Bristol Myers Squibb, 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. N. Matsubara: Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Research Funding: Astellas Pharma, AstraZeneca, Bayer, Chugai Pharma, Eisai, Janssen, Lilly, MSD, Pfizer, PRA Health Science, Roche, Seagen, Taiho, Takeda; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: Sanofi. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Pfizer, Myovant, Novartis, AstraZeneca, Merck; Financial Interests, Institutional, Local PI: Novartis, Astellas, bayer, janssen, sanofi, bms, amgen, pfizer, Merck; Financial Interests, Institutional, Coordinating PI: AstraZeenca. U. De Giorgi: Financial Interests, Personal, Advisory Board: Pfizer, BMS, MSD, PharmaMar, Astellas, Bayer, Ipsen, Novartis, EISAI, Janssen; Financial Interests, Personal, Invited Speaker: Roche, BMS, Astrazeneca, Merck; Financial Interests, Institutional, Research Grant: Astrazeneca, Sanofi, Roche. P.C. Fong: Financial Interests, Personal, Advisory Board: P.C.C.F. reports a consulting or advisory role for MSD and travel, accommodations and/or expenses from Pfizer. S. Zschäbitz: Financial Interests, Personal and Institutional, Invited Speaker: Amgen; Financial Interests, Personal and Institutional, Advisory Board: Astellas, Bayer, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Amgen, Bayer; Financial Interests, Personal, Advisory Board: Eisai, Janssen, Novartis, Gilead, Ipsen; Financial Interests, Institutional, Advisory Board: Bristol Myers Squibb. J.M. Piulats Rodriguez: Financial Interests, Personal, Advisory Board: Janssen, Astellas, Roche, BMS, MSD, BeiGene, VCN, AstraZeneca, Immunocore, Novartis; Financial Interests, Personal and Institutional, Research Grant: BMS, Pfizer, Janssen, BeiGene, Mirati, Immunocore, Regeneron. S.M. Yip: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Hoffman-La Roche, Ipsen, Janssen, Merck, Novartis, OncoHelix, Pfizer. L. DeAnnuntis: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. X. Lin: Financial Interests, Personal, Full or part-time Employment: Pfizer Inc.; Financial Interests, Personal, Stocks or ownership: Pfizer Inc. D. Laird: Financial Interests, Personal, Advisory Board: A.D.L. is an employee of Pfizer and may hold Pfizer stock/stock options. M. Kalac: Financial Interests, Personal, Advisory Board: M.K. is an employee of Pfizer and may hold Pfizer stock/stock options. 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. All other authors have declared no conflicts of interest.