Duke Cancer Institute, Durham, NC
Landon Carter Brown , Susan Halabi , Joseph Schonhoft , Jun Luo , David M. Nanus , Paraskevi Giannakakou , Daniel Costin Danila , Patrick Healy , Monika Anand , Jason Somarelli , Howard I. Scher , Rick Wenstrup , William R. Berry , Scott T. Tagawa , Emmanuel S. Antonarakis , Daniel J. George , Andrew J. Armstrong , Russell Zelig Szmulewitz
Background: While AR-V7 is a known driver of hormonal resistance, most men with mCRPC lack AR-V7 detection and commonly experience cross-resistance to abiraterone and enzalutamide (abi/enza). Loss of AR dependence through neuroendocrine (NE) differentiation or chromosomal instability (CIN) may explain AR therapy cross-resistance in additional men. Methods: PROPHECY was a multicenter prospective study of men with poor risk mCRPC starting abi/enza. We assessed Epic CTC AR-V7, CIN and NE phenotypes before abi/enza and at progression. Radiographic/clinical progression free survival (PFS) and overall survival (OS) were associated with CIN (>3 CTCs) and NE (>3 CTCs) CTC phenotypes using the proportional hazards model adjusting for Cellsearch CTC, AR-V7, and clinical risk score. Results: 118 men with mCRPC starting on abi/enza were enrolled; 106 had evaluable CTCs for AR-V7, CIN, and NE on the Epic platform. Of these, 22.6% and 9.4% of men exhibited high CTC CIN and NE scores, respectively. High pre-treatment CIN and NE phenotypic scores were observed in 63 and 27% of AR-V7 (+) and in 17 and 7% of AR-V7 (-) men. CTC CIN phenotype but not NE phenotype was associated with a lower confirmed PSA response rate and OS (TABLE) with abi/enza, adjusting for CTC number, AR-V7 and risk score. Conclusions: A high chromosomal instability CTC phenotype is associated with worse outcomes in men with mCRPC treated with abi/enza and warrants further study as a prognostic or predictive biomarker. Clinical trial information: NCT02269982
Chromosomal Instability Phenotype n=106 | Neuroendocrine Phenotype n= 106 | |||
---|---|---|---|---|
Positive | Negative | Positive | Negative | |
All Men | 24 (22.6%) | 82 (77.4%) | 10 (9.4%) | 96 (90.6%) |
Epic Nuclear AR-V7 (+) | 7 (63.6%) | 4 (36.3%) | 3 (27.3%) | 8 (72.3%) |
Median PFS (mo; 95% CI) | 4.1 (2.4-5.7) | 6.6 (4.1-8.5) | 3.3 (1.1-5.7) | 5.9 (4.1-7.8) |
HR* (95% CI) | 2.1 (1.3-3.5) | 2.1 (1.1-4.1) | ||
HR**(95% CI) | 1.1 (0.6-2.3) | 1.0 (0.4-2.4) | ||
Median OS (mo; 95% CI) | 11.5 (7.2-14.9) | 25.0 (18.5-28.0) | 8.3 (1.3-25.0) | 20.0 (16.9-25.8) |
HR*(95% CI) | 3.4 (2.0-5.6) | 2.4 (1.2-4.7) | ||
HR** (95% CI) | 2.1 (1.1-4.1) | 0.8 (0.4-1.8) | ||
≥ 50% confirmed PSA decline (95% CI) | 16% (3-40) | 30% (19-42) | 25% (3-65) | 27% (17-38) |
*univariate, **adjusted for Cellsearch CTCs (>5), AR-V7, risk score
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