Abstract 73P
Background
Mutations in homologous recombination repair genes (HRRm) (eg, BRCAm) are found in mCRPC and associated with response to PARP1 inhibitors including ola. Pembro + ola showed antitumor activity and acceptable tolerability in molecularly unselected patients (pts) with docetaxel-pretreated mCRPC (phase 1/2 KEYNOTE-365 study, cohort A [NCT02861573]). We evaluated the prevalence of BRCAm and HRRm and their association with antitumor activity.
Methods
Docetaxel-pretreated pts in cohort A of KEYNOTE-365 received pembro 200 mg IV Q3W + ola 400-mg capsule or 300-mg tablet PO BID. Antitumor activity was evaluated via PSA response rate (≥50% reduction from baseline) and ORR per RECIST v1.1 by central review. ctDNA biomarker studies used Guardant Health (GH) 360 or GH Omni assays; FFPE tissue analyses used FoundationOne®CDx (F1CDx).
Results
BRCAm was detected in 3/98 (3%) pts with valid ctDNA results (GH360 or GH Omni); HRRm was detected in 14/59 (24%, GH Omni) pts. BRCAm and HRRm were detected with F1CDx in 4/41 (10%) and 12/41 (29%) pts, respectively. There was high concordance between GH assays and F1CDx for determination of BRCA (98% agreement) and HRR (87% agreement) mutational status. In the treated population (N = 102), PSA response was 50% (2/4 pts [95% CI, 6.8%-93.2%]) in BRCAm pts (detected using either platform) and 14% (13/95 [7.5%-22.3%]) in non-BRCAm pts. PSA response was 22% (4/18 [6.4%-47.6%]) in HRRm and 13% (7/52 [5.6%-25.8%]) in non-HRRm pts. In the RECIST-measurable population (N = 58), ORR was 33% (1/3 [0.8%-90.6%]) in BRCAm and 6% (3/53 [1.2%-15.7%]) in non-BRCAm; ORR was 8% (1/12 [0.2%-38.5%]) in HRRm and 3% (1/30 [0.1%-17.2%]) in non-HRRm pts.
Conclusions
There was high concordance between GH ctDNA assays and F1CDx for the detection of BRCAm and HRRm. Encouraging PSA and overall response rates were observed in pts with BRCAm/HRRm status. Compared with pembro (KN199 Cohort 1/2: ORR = 5%) and ola (TOPARP-A: composite response rate = 6% in non-HRRm pts) monotherapies, pembro + ola may improve PSA response rate regardless of HRRm status. Caution should be used when interpreting these results because of small sample sizes.
Clinical trial identification
NCT02861573. Release date: April 10, 2016.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Lei Bai, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
E. Yu: Financial Interests, Personal, Advisory Role: Bayer, Clovis, Janssen, Merck, Sanofi, AbbVie, Advanced Accelerator Applications, Exelixis; Financial Interests, Personal, Research Grant: Bayer, Dendreon, Merck, Pharmacyclics, SeaGen, Inc., Advanced Accelerator Applications, Daiichi Sankyo, Taiho, Blue Earth. J.M. Piulats: Financial Interests, Personal, Advisory Role: MSD, Janssen, BMS, Roche, Astellas, Bayer, BeiGene, VCN, Immunocore; Financial Interests, Personal, Research Grant: MSD, Janssen, BeiGene, Novartis. G. Gravis: Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Institutional, Advisory Role: Janssen, Pfizer, Alliance Merck-Pfizer, AAA; Financial Interests, Personal, Speaker’s Bureau: Astellas; Financial Interests, Institutional, Invited Speaker: MSD, Janssen, Amgen, BMS, Sanofi; Financial Interests, Institutional, Research Grant: Janssen; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Personal, Other, Travel Expenses: BMS, Janssen, Sanofi. P. Fong: Financial Interests, Personal, Advisory Role: MSD, Pfizer. T. Todenhöfer: Financial Interests, Personal, Advisory Role: Amgen, Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Pfizer, Roche. B. Laguerre: Financial Interests, Personal, Other, Honoraria: Pfizer, AstraZeneca, Janssen, Astellas, Ipsen, MDS, Roche; Financial Interests, Personal, Invited Speaker, Travel Expenses: Pfizer, Novartis, BMS. J. Arranz: Financial Interests, Personal, Advisory Role: BMS, Astellas, MSD, Pfizer, Merck; Financial Interests, Institutional, Research Grant: BMS (SOGUG). S. Oudard: Financial Interests, Personal, Other, Honoraria: Pfizer, Sanofi, Novartis; Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Genentech, Sanofi; Financial Interests, Personal, Research Grant: AstraZeneca, BMS, Sanofi; Financial Interests, Personal, Other, Travel Expenses: Astellas, AstraZeneca, Bayer, BMS, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, Genentech, Sanofi. C. Massard: Financial Interests, Personal, Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm Group, Genentech/Roche, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, Orion, Taiho Pharmaceuticals, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals. J. Carles: Financial Interests, Personal, Advisory Role: Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Johnson & Johnson, MSD Oncology, Novartis (AAA). Pfizer. Roche, Sanofi; Financial Interests, Personal, Speaker’s Bureau, Expert Testimony: Astellas Pharma, Bayer, Johnson & Johnson; Financial Interests, Personal, Other, Travel Expenses: BMS, Ipsen, Roche, AstraZeneca; Financial Interests, Institutional, Research Grant: AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, Inc., Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim España, S.A., Bristol Myers Squibb Intern. M. Huang: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck. Y. Li: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck. P. Qiu: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck. C.H. Poehlein: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck; Financial Interests, Personal and Institutional, Stocks/Shares: Merck; Financial Interests, Personal and Institutional, Leadership Role: Merck. C. Schloss: Financial Interests, Personal and Institutional, Full or part-time Employment: Merck. J. de Bono: Financial Interests, Personal, Other, Honoraria, Travel Expenses: 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; Financial Interests, Personal, Advisory Role: 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; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals; Financial Interests, Personal, Royalties, Licensing; Patent: Self. All other authors have declared no conflicts of interest.