Circulating tumour cell (CTC) enumeration and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) treated with xaluritamig

BackgroundXaluritamig, a novel STEAP1 x CD3 XmAb® 2+1 T-cell engager, showed initial safety and efficacy in patients (pts) with mCRPC in the first-in-human dose exploration trial. In prostate cancer, enumeration of CTC counts before and during treatment provides valuable prognostic information. This is the first report of OS and CTC results from dose exploration.MethodsEligible pts had mCRPC refractory to prior novel hormonal therapy and 1–2 taxane regimens, ECOG PS 0–1, and adequate organ function. Xaluritamig was administered as an IV infusion with increasing doses (0.001–2.0 mg). CellSearch CTC testing was performed longitudinally, and CTC conversion was determined as CTC0 (decrease from CTC >0 to 0) and CTC5 (decrease from CTC ≥5 to <5). Prognostic markers tested were alkaline phosphatase (ALP), lactate dehydrogenase, hemoglobin, ECOG PS, prostate-specific antigen (PSA), and presence of liver metastases at baseline.ResultsA total of 97 pts received ≥1 dose of xaluritamig and had available serial PSA (N=95) and CTC counts (N=67). At a median follow-up of 23.5 (range: 0.5–37.9) months, median OS was 17.4 (95% CI: 13.5–21.9) months. Of the 67 pts, 54 were CTC conversion-evaluable, while 13 had 0 CTCs at baseline. CTC conversion mostly occurred by week 4, and CTC 0 occurred in 26/54 pts (48%) in dose-exploration, of which 58% (14/24) occurred in high-dose cohorts. Of the 95 PSA response evaluable pts, 51 (54%) achieved a PSA 50 response. PSA 50 response and CTC conversion were also significantly associated with OS (Table). Table: 1610P Significant prognostic markers for OS in univariate analysis Prognostic markers Evaluable pts (N) Hazard ratio for OS (95% CI) Nominal log-rank p-value Baseline liver metastases 97 2.6 (1.4–4.8) 0.0011 Elevated baseline ALP 97 1.9 (1.1–3.2) 0.018 High baseline CTCs (≥5) 67 3.7 (1.9–7.3) <0.0001 CTC conversion on treatment 54 0.52 (0.27–1.0) 0.045 PSA 50 response on treatment 95 0.57 (0.33–0.99) 0.0446 ConclusionsXaluritamig showed prolonged OS relative to historic benchmarks in heavily pretreated pts with poor prognostic features. CTC enumeration is highly prognostic of OS at baseline, and CTC conversion and PSA declines may predict response from xaluritamig treatment. Further validation is warranted as CTCs may guide future clinical development of xaluritamig by early identifying the treatment benefit in pts.Clinical trial identificationNCT04221542.Editorial acknowledgementMedical writing support was provided by Manoj Kumar Goyal, PhD, of Cactus Life Sciences (part of Cactus Communications) and funded by Amgen Inc.Legal entity responsible for the studyAmgen Inc. Thousands Oaks, CA, USA.FundingAmgen Inc. Thousands Oaks, CA, USA.DisclosureA.J. Armstrong: Financial Interests, Personal, Other, Consultant: Astellas; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Merck, Bayer, Janssen, Myovant, Telix, Z Alpha; Financial Interests, Institutional, Coordinating PI: Pfizer, Janssen, BMS, Bayer, Astellas, Pathos; Financial Interests, Institutional, Local PI: Merck, Amgen; Financial Interests, Institutional, Steering Committee Member: AstraZeneca. L.J. Appleman: Financial Interests, Institutional, Research Grant: Amgen. D.C. Danila: Financial Interests, Institutional, Research Grant: U.S. Department of Defense; Financial Interests, Institutional, Research Funding: ASCO, The Prostate Cancer Foundation, Stand Up To Cancer, Amgen Inc., Janssen Research & Development, Astellas, Medivation, Agensys, Genentech, CreaTV; Financial Interests, Personal, Advisory Role: Angle LLT, Janssen Research & Development, Astra- Zeneca, BioView Ltd., Clovis, Astellas, Medivation, Pfizer, Agensys, Merck. C. Lin: Financial Interests, Personal, Other, Travel support: BeiGene, Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Blueprint Medicines, Bristol Myers Squibb, Daiichi Sankyo, Novartis, AbbVie, PharmaEngine, Merck KGaA, Boehringer Ingelheim, Anbogen, IMPACT Therapeutics; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Roche; Financial Interests, Personal, Other, Travel Support: IMPACT Therapeutics; Financial Interests, Institutional, Other, Local principal investigator: Nuvalent. J.L. Lee: Financial Interests, Personal, Advisory Board: Astellas Korea, AstraZeneca, Bristol Myers Squibb Korea, MSD, Merck; Financial Interests, Personal, Stocks/Shares: Merck, Johnson and Johnson, Amgen, Black Diamond Therapeutics, Zymeworks, Karyopharm Therapeutics; Financial Interests, Institutional, Local PI: Pfizer, Janssen, Novartis, Bristol Myers Squibb, Genentech, Roche, AstraZeneca, MSD, Merck, Bayer Shering Pharma, Seagen, GI Innovation, Amgen, Oscotec. 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. P.J. Ward: Financial Interests, Personal, Advisory Board: Amgen, Fresenius Kabi. D.W. Pook: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Advisory Board: BMS, MSD, Ipsen, Pfizer, Eisai, Astellas; Financial Interests, Institutional, Local PI: BMS, Astellas, Roche, MSD, Amgen; Financial Interests, Institutional, Coordinating PI: Pfizer, Ipsen. M. Kim: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck Sharp & Dohme, Bristol Myers Squibb/Ono Pharmaceutical, Ipsen, Roche, Janssen, Astellas, Eisai, Bayer, Pfizer, Merck, Boryung Corporation, Yuhan Corporation. T.B. Dorff: Financial Interests, Personal, Advisory Board: AstraZeneca, Janssen, Sanofi, Bayer. S.C. Fischer: Financial Interests, Institutional, Invited Speaker: Janssen; Financial Interests, Institutional, Advisory Board: Ipsen; Financial Interests, Institutional, Coordinating PI: MSD, Astellas; Other, Travel support: Bayer. L.G. Horvath: Financial Interests, Personal, Advisory Board, Honorarium donated back to Chris O'Brien Lifehouse (My hospital): Imagion Biosystems; Financial Interests, Institutional, Invited Speaker: Astellas, Janssen, Amgen; Financial Interests, Institutional, Advisory Board: Astellas, Bayer; Financial Interests, Institutional, Invited Speaker, Bayer paid for travel to Lisbon APEX meeting and accommodation. I gave 3 talks and honorarium paid to be institution: Bayer; Financial Interests, Personal, Member of Board of Directors, No payment: ANZUP (Australia and New Zealand Urogenital and Prostate) Clinical Trials Group; Financial Interests, Personal, Full or part-time Employment, I am a medical oncologist, Director of Research and Chief Clinical Officer of this cancer centre: Chris O'Brien Lifehouse; Financial Interests, Personal, Full or part-time Employment, I am a member of the Garvan Faculty and Laboratory Head: Garvan Institute of Medical Research; Financial Interests, Personal, Stocks/Shares, Stock options: Imagion Biosystems; Financial Interests, Personal, Stocks/Shares: My Emergency Doctor; Financial Interests, Institutional, Other, I am inventor of a patent lead by my institution above: International (PCT) Patent Application No. PCT/AU2023/050849Prognostic Markers (plasma lipid prognostic signature in metastatic prostate cancer).Inventors: Horvath L, Meikle P, Scheinberg S, Lin HM, Sullivan D: Chris O'Brien Lifehouse; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Local PI, MK7684-001MK3475-991: MSD; Financial Interests, Institutional, Local PI, AMG160 Phase 1AMG509 Phase 1AMG757 Phase 1: Amgen; Financial Interests, Institutional, Local PI, 9785-CL-0335 (ARCHES): Astellas; Financial Interests, Institutional, Local PI, SHR3680-002: Jiangsu Hengrui Medicines; Financial Interests, Institutional, Local PI, TALAPRO2, TALAPRO3: Pfizer; Financial Interests, Institutional, Local PI, CYCLONE-2, CYCLONE-3: Eli Lilly; Financial Interests, Institutional, Steering Committee Member, ENZAMET, ENZARAD, DASL-HiCAP, GUIDE, ANZAdapt: ANZUP; Financial Interests, Institutional, Local PI, GALAHADACISPrevalence: Janssen-Cilag; Financial Interests, Institutional, Local PI, GSK204697: GSK; Financial Interests, Institutional, Local PI, XL184-021: Exelexis; Financial Interests, Institutional, Local PI, BGB-A317BGB-283BGB-A317-290: BeiGene; Financial Interests, Institutional, Local PI, FPT155-001: Five Prime; Financial Interests, Institutional, Local PI, AB928CSP0003: ARCUS; Financial Interests, Institutional, Local PI, ATG-017 and ATG-019: Antagene; Financial Interests, Institutional, Local PI, JANUX007: Janux; Financial Interests, Institutional, Local PI, Petranha: Astrazeneca; Financial Interests, Institutional, Local PI, ENZAMET, ENZA-P, Upfront PSMA, ANZAdapt, GUIDE: ANZUP; Financial Interests, Institutional, Local PI, HP-518-CS-001: Hinova; Financial Interests, Institutional, Local PI, JANX007: Janux Therapeutics; Non-Financial Interests, Leadership Role, Professor of Medical Oncology (Genitourinary cancer): University of Sydney; Non-Financial Interests, Leadership Role, Adjunct Professor: University of New South Wales. Z. Yang: Financial Interests, Personal and Institutional, Full or part-time Employment: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen. B.E. Decato, J.M. Englert, K.M. Smith, M. Lolkema: Financial Interests, Personal and Institutional, Full or part-time Employment: Amgen; Financial Interests, Personal, Stocks/Shares: Amgen. W.K. Kelly: Other, Personal and Institutional, Other: Amgen, Exelixis, Seagen, Novartis, BioClin, Roche, Regeneron, Janssen, Bayer; Financial Interests, Personal, Other, personal fee: Janssen, Bayer. All other authors have declared no conflicts of interest.