Values of alkaline phosphatase at the diagnosis of castration resistance and response to primary androgen deprivation therapy as predictors of subsequent metastasis in non-metastatic castration-resistant prostate cancer
Among various therapeutic options available for metastatic castration-resistant prostate cancer (mCRPC), only apalutamide and enzalutamide have shown evidences of improved metastasis-free survival (MFS) for non-metastatic castration-resistant prostate cancer (nmCRPC). However, there is a paucity of evidence to indicate who may be targeted for aggressive therapy among patients with nmCRPC. The objectives of this retrospective study were to explore predictors of metastasis in patients with nmCRPC and to identify a subpopulation of patients with nmCRPC who may benefit from aggressive therapy.
A total of 115 patients with CRPC who had no metastasis detected at the time of diagnosis of CRPC were included in this retrospective study. All patients were treated at Jikei University and its affiliated hospitals. The primary outcome measure was MFS from the time of diagnosis of CRPC. Predictors of MFS were also explored with a multivariate Cox hazard model.
The median observation period after diagnosis of CRPC was 30 months (range 2–143 months). Kaplan–Meier analysis revealed a median MFS of 76. Multivariate analysis demonstrated that low alkaline phosphatase (ALP) values at diagnosis of CRPC and favorable response to primary androgen deprivation therapy (ADT) were significant predictors of longer MFS (P = 0.011, and 0.031, respectively).
Results of this study suggest that high ALP values at diagnosis of CRPC and poor response to primary ADT may predict the propensity of metastasis in patients with nmCRPC. Further prospective studies will be required enrolling more patients to confirm our findings.
KeywordsMetastasis-free survival (MFS) Non-metastatic Castration-resistant prostate cancer (nmCRPC) Alkaline phosphatase (ALP) Retrospective study
Metastatic castration-resistant prostate cancer
Non-metastatic castration-resistant prostate cancer
Androgen deprivation therapy
Androgen receptor axis targeting
Magnetic resonance imaging
PSA doubling time
White blood cell
- 68 Ga-PSMA
68 Ga-labeled prostate-specific membrane antigen
Positron emission tomography
The authors thank Prof. Shin Egawa and Dr. Takahiro Kimura at Jikei University School of Medicine for their valuable comments and cooperations.
KM: project development, data collection, data analysis, manuscript writing/editing; TK: project development, data analysis, manuscript writing/editing; WF: data collection; KI: data collection KS: data collection; GK: data collection; TY: project development; HS: project development; JM: project development; TS: project development; KM: project development; TH: project development; KE: project development; SE: project development, manuscript writing/editing.
No founding sources were obtained for this study.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Statement of human rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Jikei University School of Medicine (30-416(9437)) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
- 8.Hoskin P, Sartor O, O'Sullivan JM et al (2014) Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol 15(12):1397–1406. https://doi.org/10.1016/s1470-2045(14)70474-7 (PMID: 25439694) CrossRefGoogle Scholar
- 11.Leibowitz-Amit R, Templeton AJ, Omlin A et al (2014) Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer. Ann Oncol 25(3):657–662. https://doi.org/10.1093/annonc/mdt581 (PMID: 24458472 PMCID: PMC4433513) CrossRefGoogle Scholar
- 15.Scher HI, Halabi S, Tannock I et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26(7):1148–1159. https://doi.org/10.1200/jco.2007.12.4487 (PMID: 18309951 PMCID: PMC4010133) CrossRefGoogle Scholar
- 18.Ryan CJ, Crawford ED, Shore ND et al (2018) The IMAAGEN study: effect of abiraterone acetate and prednisone on prostate specific antigen and radiographic disease progression in patients with nonmetastatic castration resistant prostate cancer. J Urol 200(2):344–352. https://doi.org/10.1016/j.juro.2018.03.125 (PMID: 29630978) CrossRefGoogle Scholar
- 20.Yu EY, Miller K, Nelson J et al (2012) Detection of previously unidentified metastatic disease as a leading cause of screening failure in a phase III trial of zibotentan versus placebo in patients with nonmetastatic, castration resistant prostate cancer. J Urol 188(1):103–109. https://doi.org/10.1016/j.juro.2012.03.008 (PMID: 22583636 PMCID: PMC3473078) CrossRefGoogle Scholar
- 21.Wolfgang P, Fendler MW, Iravani A et al (2018) PSMA-PET results in a nonmetastatic castration-resistant prostate cancer SPARTAN-like population that is negative by conventional imaging. In: 19th Annual meeting of the Society of Urologic Oncology 2018Google Scholar
- 22.Chi KN, Kheoh T, Ryan CJ et al (2016) A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Ann Oncol 27(3):454–460. https://doi.org/10.1093/annonc/mdv594 (PMID: 26685010 PMCID: PMC4769990) CrossRefGoogle Scholar
- 23.Loriot Y, Eymard JC, Patrikidou A et al (2015) Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer. Eur J Cancer 51(14):1946–1952. https://doi.org/10.1016/j.ejca.2015.06.128 (PMID: 26208462) CrossRefGoogle Scholar
- 25.Smith MR, Cook R, Lee KA et al (2011) Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer 117(10):2077–2085. https://doi.org/10.1002/cncr.25762 (PMID: 21523719 PMCID: PMC3116053) CrossRefGoogle Scholar
- 26.Smith MR, Saad F, Oudard S et al (2013) Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analysis by baseline prostate-specific antigen doubling time. J Clin Oncol 31(30):3800–3806. https://doi.org/10.1200/jco.2012.44.6716 (PMID: 24043751 PMCID: PMC3795889) CrossRefGoogle Scholar