Abstract 1368P
Background
TALAPRO-1 enrolled men with progressive mCRPC, measurable soft-tissue disease, and tumor DDRm involved directly or indirectly in homologous recombination repair (11-gene panel). Enrolled men had received 1–2 taxane-based chemotherapy regimens and progressed on ≥1 novel hormonal therapy. Confirmed objective response rate (primary endpoint; per RECIST 1.1; blinded independent central review [BICR]) was 29.8%. The molecular bases of prolonged clinical benefit with poly(ADP-ribose) polymerase inhibitors are incompletely understood, although limited evidence suggests that patients exhibiting large deletions in BRCA genes may experience extended benefit. Exploratory post hoc biomarker analyses assessed tumor genetics associated with prolonged antitumor benefit in TALAPRO-1.
Methods
Tumor alterations were assessed using FoundationOne®CDx. Zygosity of tumor alterations was predicted using somatic-germline-zygosity. Prolonged benefit was assessed as radiographic progression-free survival ([rPFS]; RECIST 1.1/PCWG3; BICR) time to event or censoring. Data cutoff was Sept 4, 2020 (primary completion date).
Results
Of 104 men in the efficacy population, 16 had rPFS of ≥12 months. Of their 16 tumors, 15 (94%) had BRCA2 alterations, including 10 large structural variants (9 copy number loss, 1 rearrangement) and 5 short variants (SV; 4 homozygous). In contrast, only 6/27 (22%) men with rPFS <2.0 months exhibited BRCA2 alterations (1 rearrangement, 1 non-defined, and 4 SV with 2 homozygous). Of 61 men with rPFS <12 months but ≥2 months, 36 (59%) had BRCA2 alterations (9 copy number loss, 1 rearrangement, 21 SV [11 homozygous], 2 multiple alterations [1 homozygous], and 3 not defined). Conversely, TP53 alterations were less common for men with rPFS ≥12 months vs <2 months (2/16 vs 14/27; P=0.02 Fisher’s exact test, 2-tails), potentially reflecting negative prognosis or a subgroup less sensitive to PARP inhibition.
Conclusions
Based on these retrospective, exploratory analyses of TALAPRO-1, men exhibiting prolonged benefit typically exhibited BRCA2 copy number loss or homozygous alterations, and lacked TP53 alterations.
Clinical trial identification
NCT03148795.
Editorial acknowledgement
This study was sponsored by Pfizer. Editorial support was provided by Maddie Higgins, MBiolSci, of CMC AFFINITY, McCann Health Medical Communications, and was funded by Pfizer.
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc.
Disclosure
J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Vertex Pharmaceuticals, Sanofi Aventis, Sierra Oncology, Taiho, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. E. Castro Marcos: Financial Interests, Personal, Advisory Board: Astellas, AstraZeneca, Janssen, MSD, Bayer, Pfizer; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Janssen, Clovis, Pfizer, Pfizer; Financial Interests, Institutional, Funding: AstraZeneca, Pfizer; Financial Interests, Institutional, Research Grant: Janssen, Bayer; Financial Interests, Institutional, Invited Speaker: Janssen, Pfizer. D.A. Laird: Financial Interests, Institutional, Full or part-time Employment: Pfizer; Financial Interests, Institutional, Stocks/Shares: Pfizer. K. Fizazi: Financial Interests, Institutional, Advisory Board: Astellas, Bayer, Janssen, AAA, MSD, AstraZeneca, Novartis/AAA, Pfizer; Financial Interests, Institutional, Invited Speaker: Astellas, Bayer, Janssen, Sanofi, MSD, AstraZeneca, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Curevac, Orion; 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. T. Dorff: Financial Interests, Personal, Advisory Board: Seagen, AbbVie, AstraZeneca; Financial Interests, Institutional, Advisory Board: Exelixis; Financial Interests, Personal, Other, drafted educational content (unbranded): Astellas; Financial Interests, Institutional, Research Grant: Pfizer. S. Zhao: Financial Interests, Institutional, Other, Consulting Fees: AstraZeneca, EMD Serono, Exelixis, Janssen, Pfizer, Sanofi, Seattle Genetics; Financial Interests, Institutional, Research Grant: Pfizer. I.M. van Oort: Financial Interests, Institutional, Other, Consulting Fees: AAA Novartis, Astellas Pharma, Bayer, Ipsen, Janssen, MSD/AstraZeneca; Financial Interests, Institutional, Research Grant: Astellas Pharma, Bayer. F. Calabrò: Financial Interests, Institutional, Other, Consulting Fees: Merck Sharp & Dohme Oncology, Pfizer. S. Pignata: Financial Interests, Personal, Advisory Board: Roche, AZ, MSD, Clovis, GSK, PharmaMar; Financial Interests, Institutional, Funding: Roche, MSD, Pfizer, AZ. L. Geczi: Financial Interests, Institutional, Invited Speaker: Merck, BMS, Pfizer; Financial Interests, Institutional, Other, Travel, Accommodation Expenses: Merck, BMS, Pfizer. P. Barthelemy: Financial Interests, Institutional, Advisory Board: Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen-Cilag, Merck KGaA, MSD, MSD Oncology, and Pfizer; Financial Interests, Institutional, Other, travel expenses, including accommodation: Astellas Pharma, Bristol Myers Squibb, Ipsen, Janssen-Cilag, MSD, Pfizer. D. Kilari: Financial Interests, Personal, Other, Honoraria: Exelixis; Financial Interests, Personal, Advisory Board: Exelixis, Sanofi, Merck Sharp & Dohme, Myovant Sciences; Financial Interests, Personal, Speaker’s Bureau: Janssen, Exelixis, Astellas Pharma, Aveo Oncology; Financial Interests, Institutional, Research Grant: Astellas Pharma, Exelixis, Genentech; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Exelixis, Janssen Recipient, Astellas Pharma, Aveo Oncology. J.F. Hopkins: Financial Interests, Institutional, Full or part-time Employment: Foundation Medicine Inc.; Financial Interests, Institutional, Stocks/Shares: Roche Holding AG. H. Chen, C.G. Healy: Financial Interests, Institutional, Ownership Interest: Pfizer; Financial Interests, Institutional, Full or part-time Employment: Pfizer. J. Chelliserry: Financial Interests, Institutional, Full or part-time Employment: Pfizer; Financial Interests, Institutional, Stocks/Shares: Pfizer. G.V. Scagliotti: Financial Interests, Personal and Institutional, Other, commercial interest, relationship(s), and Honoraria: AstraZeneca, Eli Lilly, Johnson & Johnson, MSD, Novartis, Pfizer, Roche, and Takeda; Financial Interests, Institutional, Advisory Board: AstraZeneca, BeiGene, and Eli Lilly; Financial Interests, Institutional, Research Grant: Eli Lilly, MSD, and Tesaro; Financial Interests, Institutional, Other, Travel and Accommodation: Bayer. 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, Invited Speaker: 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. All other authors have declared no conflicts of interest.