Abstract 138P
Background
Phase 2 TALAPRO-1 enrolled patients (pts) with RECIST1.1 measurable soft tissue disease, progressive CRPC, and DDRalt likely to sensitize to PARP inhibitors (PARPi) (ie, ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C). Pts received ≥1 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy. Primary endpoint is objective response rate (ORR; central review). Based on a prior interim analysis (IA) of 43 evaluable pts enrolled by 02/12/19, TALA showed encouraging antitumor activity and was well tolerated. This interim biomarker analysis was to assess germline/somatic origin of tumor DDRalt (tDDRalt) and associations with efficacy.
Methods
Tumor tissue was tested using FoundationOne®. Saliva samples were sequenced using Ambry CustomNext-Cancer panel, which included 9/11 genes in the tDDR panel. Known/likely pathogenic tDDR variants (tDDRalt) used to support molecular eligibility for study were categorized as of germline (also present in saliva), somatic (not present in saliva), or unknown origin. Categorization was limited to short variants. This IA contained investigator-entered data (“as-is”, cutoff 12/12/19).
Results
Of 37 evaluable pts, with results from both tumor and investigational germline analysis, 20 (54%) had ≥1 tDDRalt of germline origin, 16 (43%) exhibited only tDDRalt of somatic origin, and 1 (3%) was nonassessable for origin (FANCA not in germline panel). The most common tDDRalt in the 37 pts were BRCA2 (11 germline; 7 somatic) and ATM (3 germline; 6 somatic). Observed ORR was numerically higher for pts with tDDRalt of germline origin (7/20 [35%]) than with only somatic DDRalt (1/16 [6.3%]), although this difference was not significant (odds ratio [95% CI] 8.1 [0.8–387.7]; P = 0.053, 2-sided Fisher’s exact test).
Conclusions
Based on this IA, prostate cancers bearing germline DDRalt may be more sensitive to TALA than those bearing only somatic DDRalt. Potential reasons include possible gene-specific imbalances in origin of alterations and/or sensitivity to PARPi, and lower tumor subclonality of germline DDRalt.
Clinical trial identification
NCT03148795.
Editorial acknowledgement
Legal entity responsible for the study
Pfizer.
Funding
Pfizer.
Disclosure
N. Mehra: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Astellas Pharma; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Advisory/Consultancy: Genzyme; Advisory/Consultancy, Research grant/Funding (institution): Janssen-Cilag; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD Oncology; Advisory/Consultancy, Research grant/Funding (institution): Roche; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche/Genentech; Research grant/Funding (institution): Sanofi. K. Fizazi: Advisory/Consultancy, Travel/Accommodation/Expenses: Amgen; Honoraria (self), Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: CureVac; Advisory/Consultancy: ESSA; Advisory/Consultancy: Janssen Oncology; Advisory/Consultancy: Orion Pharma GmbH; Advisory/Consultancy: Roche/Genentech; Honoraria (self), Advisory/Consultancy: Sanofi; Honoraria (self), Travel/Accommodation/Expenses: Janssen. A..D. Laird: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. P. Barthélémy: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: PFIZER; Advisory/Consultancy: Janssen Cilag; Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Ipsen; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy: EusaPharma; Advisory/Consultancy: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Janssen. T. Dorff: Advisory/Consultancy: Bayer; Advisory/Consultancy: Dendreon; Advisory/Consultancy: BMS; Advisory/Consultancy: Janssen; Advisory/Consultancy: Seattle Genetics. A. Stirling: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. J. Machiels: Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Debio; Honoraria (self): AstraZeneca; Honoraria (self): Innate; Honoraria (self): Nanobiotix; Honoraria (self): Bayer; Honoraria (self): Merck-Serono; Honoraria (self): MSD; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Cue pharma; Honoraria (self): Incyte; Honoraria (self): Janssen; Honoraria (self): Johnson & Johnson; Honoraria (self): ALX Oncology; Honoraria (institution): Pfizer; Honoraria (institution): Ceylyad; Honoraria (institution): MSD; Honoraria (institution): AstraZeneca; Honoraria (institution): Novartis; Honoraria (institution): KURA; Honoraria (institution): iTeos; Honoraria (institution): Roche; Honoraria (institution): Lilly; Honoraria (institution): Boehringer-Ingelheim; Honoraria (institution): Sanofi-Aventis; Honoraria (institution): Incyte; Honoraria (institution): Bayer; Honoraria (institution): Merck-Serono; Honoraria (institution): Janssen; Honoraria (institution): Johnson & Johnson; Honoraria (institution): Amgen; Honoraria (institution): Abbvie; Honoraria (institution): GlaxoSmithKline. MSD Steering committee for head and neck cancer trial (412); AstraZeneca steering committee for Head and neck trial (Kestrel); Travel expenses: Amgen, Pfizer, BMS, MSD; Board member of the Belgian Society of medical Oncology, Scientific committee of Belgian Foundation against cancer, Member of the EORTC: active investigator, Study coordinator of EORTC 1559 trial. H. Dumez: Travel/Accommodation/Expenses: Astellas; Travel/Accommodation/Expenses: Novartis; Travel/Accommodation/Expenses: Bayer; Travel/Accommodation/Expenses: Sanofi; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Janssen-Cilag; Travel/Accommodation/Expenses: Pfizer. L.A. Albacker: Full/Part-time employment: Foundation Medicine Inc.; Shareholder/Stockholder/Stock options: Roche Holdings AG. V. Renard: Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Ipsen; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Novartis. J. Hopkins: Full/Part-time employment: Foundation Medicine Inc.; Shareholder/Stockholder/Stock options: Roche Holdings AG. H. Chen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. M. Mata: Full/Part-time employment: Pfizer. N. Di Santo: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. C.G. Healy: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. I.M. van Oort: Advisory/Consultancy, Research grant/Funding (self): Astellas Pharma; Advisory/Consultancy: Janssen; Advisory/Consultancy, Research grant/Funding (self): Bayer; Advisory/Consultancy: Sanofi. C. Buttigliero: Advisory/Consultancy: Janssen. J.S. de Bono: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (institution): Bayer; Honoraria (self), Advisory/Consultancy: BioXcel Therapeutics; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (institution): Celgene; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Daiichi Sankyo; Advisory/Consultancy: Eisai; Advisory/Consultancy, Travel/Accommodation/Expenses: Genmab; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: GSK; Honoraria (self), Advisory/Consultancy: Janssen Oncology; Honoraria (self), Advisory/Consultancy: Menarini Silicon Biosystems; Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Research grant/Funding (institution): Merck Sharpe & Dohme; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Orion Pharma GmbH; Honoraria (self), Advisory/Consultancy: Pfizer; Honoraria (self), Advisory/Consultancy: Roche/Genenteh; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Sierra Oncology; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Taiho Pharmaceutical; Research grant/Funding (institution): Astex Pharmaceuticals; Research grant/Funding (institution): Cellcentric; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): MedImmune; Research grant/Funding (institution): Medivation; Travel/Accommodation/Expenses: Qiagen; Travel/Accommodation/Expenses: Vertex; Non-remunerated activity/ies, inventor, with no financial interest, for patent 8,822,438: Inventor. All other authors have declared no conflicts of interest.