title: Dynamic changes of alkaline phosphatase are strongly associated with PSA-decline and predict best clinical benefit earlier than PSA-changes under therapy with abiraterone acetate in bone metastatic castration resistant prostate cancer.
abstract: BACKGROUND
  Significant progress in treatment of metastatic castration resistant prostate cancer (mCRPC) has been made. Biomarkers to tailor therapy are scarce. To facilitate decision-making we evaluated dynamic changes of alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and prostate specific antigen (PSA) under therapy with Abiraterone.
  
  
  METHODS
  Men with bone mCRPC (bmCRPC) on Abiraterone 12/2009-01/2014 were analyzed. Dynamic ALP-, LDH- and PSA-changes were analyzed as predictors of best clinical benefit and overall survival (OS) with logistic-regression, Cox-regression and Kaplan-Meier-analysis.
  
  
  RESULTS
  Thirty-nine pre- and 45 post-chemotherapy patients with a median follow up of 14.0 months were analyzed. ALP-Bouncing can be observed very early during therapy with Abiraterone. ALP-Bouncing is defined as rapidly rising ALP-levels independent of baseline ALP during the first 2-4 weeks of Abiraterone-therapy with subsequent equally marked decline to pretreatment levels or better within 8 weeks of therapy, preceding potentially delayed PSA-decline. In univariate analysis failure of PSA-reduction ≥ 50% and failure of ALP-Bouncing were the strongest predictors of progressive disease (p = 0.003 and 0.021). Rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing were strongest predictors of poor OS, (all p < 0.001). Kaplan-Meier-analysis showed worse OS for rising ALP at 12 weeks, no PSA-reduction ≥ 50% and no ALP-Bouncing (p < 0.001). In subgroup-analysis of oligosymptomatic patients all parameters remained significant predictors of poor OS, with no PSA-reduction ≥ 50% and rising ALP at 12 weeks being the strongest (p < 0.001). In multivariate analysis PSA-reduction ≥ 50% remained an independent predictor of OS for the whole cohort and for the oligosymptomatic subgroup (both p = 0.014). No patient with ALP-Bouncing had PD for best clinical benefit. Patients with rising ALP at 12 weeks had no further benefit of Abiraterone.
  
  
  CONCLUSIONS
  Dynamic changes of ALP, LDH and PSA during Abiraterone-therapy are associated with best clinical benefit and OS in bmCRPC. ALP-Bouncing occurring earlier than PSA-changes as well as prior to equivocal imaging results and rising ALP at 12 weeks under Abiraterone may help to decide whether to discontinue Abiraterone. An external validation of these findings on a prospective cohort is planned.
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Phillip
authors.initials: P
authors.lastname: Mikah
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Laura-Maria
authors.initials: LM
authors.lastname: Krabbe
authors.affiliation: Department of Urology, Cologne University Medical Center, Kerpener Strasse 62, GB Nr. 9, D-50937, Cologne, Germany.
authors.forename: Okyaz
authors.initials: O
authors.lastname: Eminaga
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Edwin
authors.initials: E
authors.lastname: Herrmann
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Papavassilis
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Reemt
authors.initials: R
authors.lastname: Hinkelammert
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Semjonow
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany.
authors.forename: Andres-Jan
authors.initials: AJ
authors.lastname: Schrader
authors.affiliation: Department of Urology, Muenster University Medical Center, Albert-Schweitzer-Campus 1, GB A1, D-48149, Muenster, Germany. martin.boegemann@ukmuenster.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Boegemann
mesh_terms: D000368:Aged; D000469:Alkaline Phosphatase / Q000097:blood*; D000736:Androstenes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology / Q000556:secondary; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017430:Prostate-Specific Antigen / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000736:Androstenes; D014408:Biomarkers, Tumor; D007770:L-Lactate Dehydrogenase; D000469:Alkaline Phosphatase; D017430:Prostate-Specific Antigen; C089740:abiraterone
keywords: Abiraterone acetate; Outcomes; Prostate cancer; Surrogate biomarker; mCRPC