Abstract 614P
Background
In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) vs abiraterone or enzalutamide in patients (pts) with metastatic castration-resistant prostate cancer who had received docetaxel and progressed ≤ 12 months with the alternative androgen receptor-targeted agent (ARTA). Here we analyzed the morphology of CTC subtypes in a liquid biopsy.
Methods
Blood samples collected at screening (SC), Cycle 2 Day 1 (C2), and end of therapy (EOT) were blinded and sent to Epic Sciences for analysis. Chromosomal instability (CIN) within CTCs and Shannon Index were assessed using nuclear and cytoplasmic morphology. CTC phenotypes were correlated with rPFS and OS using Kaplan-Meier estimates and multivariable Cox proportional hazard models.
Results
At SC, C2, and EOT, 215, 195, and 142 samples were evaluable respectively (Table). CIN+ CTCs increased from SC to C2 to EOT in the ARTA arm, where as in the cabazitaxel arm CIN+ CTC levels were stable during treatment. In the cabazitaxel arm, pts with CIN+ CTCs at SC had significantly shorter OS and rPFS than those with CIN- CTCs. In the ARTA arm, OS and rPFS remained shorter than with cabazitaxel regardless of CIN status. Blood samples harboring CIN+ CTCs had increased morphologic diversity (higher Shannon index, P < 0.0001) and 44% had CTCs (21% of pts overall) that were small, circular, and had high nuclear to cytoplasm ratios similar to criteria for small-cell or neuroendocrine transformation. Sequencing of CTCs and staining with neuroendocrine markers will also be presented.
Conclusions
CIN+ CTCs at SC were associated with shorter OS and rPFS in the CARD study. The phenotypic diversity of detected CTCs suggests that multiple mechanisms may drive therapy resistance and that alternative therapies, combinations, or clinical trials may be more suitable for pts harboring these CTC phenotypes. Table: 614P
Median time-to-events and associated HR for rPFS and OS
| Overall N = 215 | Cabazitaxel n = 109 | ARTA n = 106 | ||||
| CIN+ | CIN- | CIN+ | CIN- | CIN+ | CIN- | |
| CIN status* at SC, n (%) | 106 (100) | 109 (100) | 47 (44) | 62 (57) | 59 (56) | 47 (43) |
| Median rPFS, months | 3.4 | 5.3 | 3.3 | 8.2 | 4.1 | 3.5 |
| HR** (95% CI) | 1.41 (1.01–1.97) | 1.90 (1.16–3.13) | 0.84 (0.52–1.38) | |||
| P value | 0.046 | 0.01 | 0.50 | |||
| Median OS, months | 9.6 | 15.8 | 8.8 | 13.9 | 7.7 | 11.2 |
| HR** (95% CI) | 1.86 (1.26–2.75) | 1.96 (1.05–3.65) | 1.57 (0.92–2.67) | |||
| P value | 0.002 | 0.03 | 0.10 |
* 1 or more CIN+ CTC present; ** Multivariate HR adjusted for PSA, LDH, ALP, Hb, presence of visceral metastases, pain, and ECOG score
Clinical trial identification
NCT02485691.
Editorial acknowledgement
Editorial support was provided by Amber Wood of Meditech Media, funded by Sanofi.
Legal entity responsible for the study
Sanofi.
Funding
Sanofi.
Disclosure
J.S. de Bono: Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Sanofi; Financial Interests, Personal, Other, Honoraria: Astellas Pharma; Financial Interests, Personal, Other, Honoraria: Pfizer; Financial Interests, Personal, Other, Honoraria: Genentech/Roche; Financial Interests, Personal, Other, Honoraria: Janssen Oncology; Financial Interests, Personal, Other, Honoraria: Menarini Silicon Biosystems; Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria: Sierra Oncology and BioXcel Therapeutics; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Genentech/Roche; Financial Interests, Personal, Advisory Role: Astellas Pharma; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Sierra Oncology; Financial Interests, Personal, Advisory Role: Menarini Silicon Biosystems; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Janssen Oncology; Financial Interests, Personal, Advisory Role: Genmab; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Personal, Advisory Role: Orion Pharma GmbH; Financial Interests, Personal, Advisory Role: Eisai and BioXCel Therapeutics. K. Pantel: Financial Interests, Personal, Other, Honoraria: Roche; Financial Interests, Personal, Other, Honoraria: Novartis; Financial Interests, Personal, Other, Honoraria: Merck; Financial Interests, Personal, Other, Honoraria: Siemens; Financial Interests, Personal, Other, Honoraria: Agena; Financial Interests, Personal, Advisory Role: Menarini Silicon Biosystems; Financial Interests, Personal, Research Grant: EFPIA partners of the EU/IMI network Cancer-ID. C.N. Sternberg: Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Other, Honoraria: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Sanofi; Financial Interests, Personal, Other, Honoraria: Astellas; Financial Interests, Personal, Other, Consultancy fees: Pfizer; Financial Interests, Personal, Other, Consultancy Fees: Merck; Financial Interests, Personal, Other, Consultancy Fees: MSD; Financial Interests, Personal, Other, Consultancy Fees: AstraZeneca; Financial Interests, Personal, Other, Consultancy Fees: Astellas Pharma; Financial Interests, Personal, Other, Consultancy Fees: Sanofi-Genzyme; Financial Interests, Personal, Other, Consultancy Fees: Roche/Genentech; Financial Interests, Personal, Other, Consultancy Fees: Incyte; Financial Interests, Personal, Other, Consultancy Fees: Medscape; Financial Interests, Personal, Other, Consultancy Fees: Clovis Oncology; Financial Interests, Personal, Other, Consultancy Fees: Foundation Medicine; Financial Interests, Personal, Other, Consultancy Fees: UroToday; Financial Interests, Institutional, Funding: Genentech/Roche; Financial Interests, Institutional, Funding: Bayer; Financial Interests, Institutional, Funding: Sanofi Genzyme; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: Medivation; Financial Interests, Institutional, Funding: Merck Sharp & Dohme; Financial Interests, Institutional, Funding: Exelixis. D. Castellano Gauna: Financial Interests, Personal, Other, Personal fees: Pfizer; Financial Interests, Personal, Other, Personal fees: Roche; Financial Interests, Personal, Other, Personal fees: Sanofi; Financial Interests, Personal, Other, Personal fees: Janssen; Financial Interests, Personal, Other, Personal fees: Astellas; Financial Interests, Personal, Other, Personal fees: Bayer; Financial Interests, Personal, Other, Personal fees: Bristol-Myers Squibb; Financial Interests, Personal, Other, Personal fees: Merck Sharp & Dohme; Financial Interests, Personal, Other, Personal fees: Merck Serono; Financial Interests, Personal, Other, Personal fees: Pierre Fabre; Financial Interests, Personal, Other, Personal fees: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Lilly. K. Fizazi: Financial Interests, Personal, Advisory Role, Honoraria: Astellas; Financial Interests, Personal, Advisory Role, Honoraria: AAA; Financial Interests, Personal, Advisory Role, Honoraria: Bayer; Financial Interests, Personal, Advisory Role, Honoraria: Essa; Financial Interests, Personal, Advisory Role, Honoraria: Janssen; Financial Interests, Personal, Advisory Role, Honoraria: Orion; Financial Interests, Personal, Advisory Role, Honoraria: Sanofi; Financial Interests, Personal, Advisory Role, Honoraria: CureVac; Financial Interests, Personal, Advisory Role, Honoraria: Sanofi; Financial Interests, Personal, Advisory Role, Honoraria: Endocyte. B. Tombal: Financial Interests, Personal, Research Grant, Personal fees: Astellas; Financial Interests, Personal, Research Grant, Personal fees: Janssen; Financial Interests, Personal, Research Grant, Personal fees: Sanofi Genzyme; Financial Interests, Personal, Research Grant, Personal fees: Amgen; Financial Interests, Personal, Research Grant, Personal fees: Ferring; Non-Financial Interests, Personal, Other, Non-Financial support: Sanofi Genzyme. J.D. Schonhoft: Financial Interests, Personal, Stocks/Shares: Epic Sciences. A. Tubbs: Financial Interests, Personal, Stocks/Shares: Epic Sciences. L. Chu: Financial Interests, Personal, Stocks/Shares: Epic Sciences. R. Wenstrup: Financial Interests, Personal, Stocks/Shares: Epic Sciences. A. Ozatilgan: Financial Interests, Personal, Full or part-time Employment: Sanofi. C. Geffriaud-Ricouard: Financial Interests, Personal, Full or part-time Employment: Sanofi. S. Macé: Financial Interests, Personal, Full or part-time Employment: Sanofi. R. de Wit: Financial Interests, Personal, Advisory Role, Consulting Role: Sanofi; Financial Interests, Personal, Advisory Role, Consulting Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role, Consulting Role: Roche/Genetech; Financial Interests, Personal, Advisory Role, Consulting Role: Bayer; Financial Interests, Personal, Research Grant, Honoraria: Sanofi; Financial Interests, Personal, Research Grant, Honoraria: Merck Sharp & Dohme; Financial Interests, Personal, Research Grant, Honoraria: Bayer; Financial Interests, Personal, Other, Advisory Fees: Astellas. All other authors have declared no conflicts of interest.