Alkaline phosphatase in metastatic castration-resistant prostate cancer: reassessment of an older biomarker
Abstract
Since most patients with metastatic castration-resistant prostate cancer (mCRPC) have bone metastases, it is important to understand the potential impact of therapies on prognostic biomarkers, such as ALP. Clinical studies involving mCRPC life-prolonging agents (i.e., sipuleucel-T, abiraterone, enzalutamide, docetaxel, cabazitaxel, and radium-223) have shown that baseline ALP level is prognostic for overall survival, and may be a better prognostic marker for overall survival than prostate-specific antigen in patients with bone-dominant mCRPC. Mechanism of action differences between therapies may partly explain ALP dynamics during treatment. ALP changes can be interpreted within the context of other parameters while monitoring disease activity to better understand the underlying pathology. This review evaluates the current role of ALP in mCRPC.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Metastasis to bone: causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2(8), 584–593 (2002).
- 2 . Cancer to bone: a fatal attraction. Nat. Rev. Cancer 11(6), 411–425 (2011).
- 3 . Evolving role of bone biomarkers in castration-resistant prostate cancer. Neoplasia 12(9), 685–696 (2010).
- 4 . Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals. J. Biol. Chem. 287(24), 20037–20046 (2012).
- 5 . Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. J. Biol. Chem. 279(5), 3662–3670 (2004).
- 6 . Targeting bone metastases in metastatic castration-resistant prostate cancer. Clin. Med. Insights Oncol. 10(Suppl. 1), 11–19 (2016).
- 7 Metastatic patterns of prostate cancer: an autopsy study of 1589 patients. Hum. Pathol. 31(5), 578–583 (2000).
- 8 Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351(15), 1502–1512 (2004).
- 9 . Tissue-nonspecific alkaline phosphatase is required for the calcification of collagen in serum: a possible mechanism for biomineralization. J. Biol. Chem. 284(7), 4594–4604 (2009).
- 10 Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin. Cancer Res. 12(11 Pt 1), 3361–3367 (2006).
- 11 Basic mechanisms responsible for osteolytic and osteoblastic bone metastases. Clin. Cancer Res. 12(20 Pt 2), 6213s–6216s (2006). • A review of the mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.
- 12 . The value of biomarkers in bone metastasis. Eur. J. Cancer Care 26(6), e12725 (2017). •• A review of the current knowledge of bone metastasis development and recent advances in biomarker research.
- 13 . Osteomimicry: how tumor cells try to deceive the bone. Front. Biosci. 2, 907–915 (2010). • A review of bone metastases and osteomimicry.
- 14 Bone metastatic LNCaP-derivative C4-2B prostate cancer cell line mineralizes in vitro. Prostate 47(3), 212–221 (2001).
- 15 . Bone metastasis: osteoblasts affect growth and adhesion regulons in prostate tumor cells and provoke osteomimicry. Int. J. Cancer 111(1), 152–159 (2004).
- 16 Human prostate cancer harbors the stem cell properties of bone marrow mesenchymal stem cells. Clin. Cancer Res. 17(8), 2159–2169 (2011).
- 17 . Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer. Cancer J. 19(1), 25–33 (2013).
- 18 Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors. J. Natl Cancer Inst. 97(1), 59–69 (2005).
- 19 Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J. Clin. Oncol. 23(22), 4925–4935 (2005).
- 20 . Using surrogate biomarkers to predict clinical benefit in men with castration-resistant prostate cancer: an update and review of the literature. Oncologist 14(8), 816–827 (2009).
- 21 Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer. Eur. Urol. 68(1), 42–50 (2015). •• Analysis of a contemporary metastatic castration-resistant prostate cancer dataset that identified bone-related parameters associated with longer survival.
- 22 Prediction of overall survival for patients with metastatic castration-resistant prostate cancer: development of a prognostic model through a crowdsourced challenge with open clinical trial data. Lancet Oncol. 18(1), 132–142 (2017).
- 23 Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy. J. Natl Cancer Inst. 105(22), 1729–1737 (2013).
- 24 Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J. Clin. Oncol. 32(7), 671–677 (2014).
- 25 . Navigating the evolving therapeutic landscape in advanced prostate cancer. Urol. Oncol. 35S, S1–S13 (2017).
- 26 Elevated alkaline phosphatase velocity strongly predicts overall survival and the risk of bone metastases in castrate-resistant prostate cancer. Urol. Oncol. 32(6), 761–768 (2014). • Retrospective study of ALP velocity as an independent predictor of overall survival and bone metastases–free survival in patients with CRPC.
- 27 Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer. Urol. Oncol. 35(7), 460.e421–460.e428 (2017).
- 28 . Present, emerging and possible future biomarkers in castration resistant prostate cancer (CRPC). Curr. Cancer Drug Targets 15(3), 243–255 (2015).
- 29 . Biomarkers for the management of castration-resistant prostate cancer: we are not there yet. Target Oncol. 12(4), 401–412 (2017). •• A review of existing and potential biomarkers for managing CRPC.
- 30 . Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy. Cancer Immunol. Immunother. 64(6), 655–663 (2015).
- 31 . Prostate cancer as a model for tumour immunotherapy. Nat. Rev. Immunol. 10(8), 580–593 (2010).
- 32 Role of antigen spread and distinctive characteristics of immunotherapy in cancer treatment. J. Natl. Cancer Inst. 109(4),
doi:10.1093/jnci/djw261 (2017). - 33 . Sipuleucel-T in the treatment of prostate cancer: an evidence-based review of its place in therapy. Core Evid. 10, 1–10 (2015).
- 34 No authors listed. Provenge® (sipuleucel-T) suspension for intravenous infusion [prescribing information]. Dendreon Corporation, WA, USA (2010).
- 35 . Abiraterone acetate: oral androgen biosynthesis inhibitor for treatment of castration-resistant prostate cancer. Drug Des. Devel. Ther. 6, 13–18 (2012).
- 36 . Clinical use of abiraterone in the treatment of metastatic castration-resistant prostate cancer. Res. Rep. Urol. 6, 97–105 (2014).
- 37 . Abiraterone in the treatment of metastatic castration-resistant prostate cancer. Cancer Manag. Res. 6, 39–51 (2014).
- 38 Biological and clinical effects of abiraterone on anti-resorptive and anabolic activity in bone microenvironment. Oncotarget 6(14), 12520–12528 (2015).
- 39 . CYP17 inhibitors in prostate cancer: latest evidence and clinical potential. Ther. Adv. Med. Oncol. 8(4), 267–275 (2016).
- 40 No authors listed. Zytiga™ (abiraterone acetate) tablets for oral administration [prescribing information]. Centocor Ortho Biotech, Inc., PA, USA (2011).
- 41 . Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer. BJU Int. 117(2), 215–225 (2016).
- 42 . Advanced prostate cancer – patient survival and potential impact of enzalutamide and other emerging therapies. Ther. Clin. Risk Manag. 10, 651–664 (2014).
- 43 Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324(5928), 787–790 (2009).
- 44 No authors listed. Xtandi® (enzalutamide) capsules for oral use [prescribing information]. Astellas Pharma US Inc., IL, USA (2012).
- 45 . Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin. Oncol. 28(4 Suppl. 15), 3–7 (2001).
- 46 . Mechanisms of action of taxanes in prostate cancer. Semin. Oncol. 26(5 Suppl. 17), 3–7 (1999).
- 47 . Tubulin-targeting chemotherapy impairs androgen receptor activity in prostate cancer. Cancer Res. 70(20), 7992–8002 (2010).
- 48 . Taxane mechanisms of action: potential implications for treatment sequencing in metastatic castration-resistant prostate cancer. Eur. Urol. 65(6), 1198–1204 (2014).
- 49 . Docetaxel down-regulates the expression of androgen receptor and prostate-specific antigen but not prostate-specific membrane antigen in prostate cancer cell lines: implications for PSA surrogacy. Prostate 69(14), 1579–1585 (2009).
- 50 No authors listed. Taxotere (docetaxel) injection concentrate, intravenous infusion [prescribing information]. Sanofi-Aventis US LLC, NJ, USA (2015).
- 51 . Diving into cabazitaxel's mode of action: more than a taxane for the treatment of castration-resistant prostate cancer patients. Clin. Genitourin. Cancer 14(4), 265–270 (2016).
- 52 . Castrate-resistant prostate cancer: postdocetaxel management. Curr. Opin. Urol. 23(3), 201–207 (2013).
- 53 . Cabazitaxel. Nat. Rev. Drug Discov. 9(9), 677–678 (2010).
- 54 No authors listed. Jevtana (cabazitaxel) injection, 60 mg/1.5 ml, for intravenous infusion only [prescribing information]. Sanofi-Aventis U.S. LLC, NJ, USA (2010).
- 55 . Significant antitumor effect from bone-seeking, alpha-particle-emitting 223Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 62(11), 3120–3125 (2002).
- 56 . Targeting of osseous sites with alpha-emitting 223Ra: comparison with the beta-emitter 89Sr in mice. J. Nucl. Med. 44(2), 252–259 (2003).
- 57 . High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin. Cancer Res. 12(20 Pt 2), 6250s–6257s (2006).
- 58 . Whole-body and microenvironmental localization of radium-223 in naive and mouse models of prostate cancer metastasis. J. Natl Cancer Inst. 108(5), djv380 (2016).
- 59 Radium-223 inhibits osseous prostate cancer growth by dual targeting of cancer cells and bone microenvironment in mouse models. Clin. Cancer Res. 23(15), 4335–4336 (2017).
- 60 Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J. Natl Cancer Inst. 105(12), 908–916 (2013).
- 61 . Sublethal exposure to alpha radiation (223Ra dichloride) enhances various carcinomas’ sensitivity to lysis by antigen-specific cytotoxic T lymphocytes through calreticulin-mediated immunogenic modulation. Oncotarget 7(52), 86937–86947 (2016).
- 62 No authors listed. Xofigo (radium Ra 223 dichloride) Injection, for intravenous use [prescribing information]. Bayer HealthCare Pharmaceuticals Inc., NJ, USA (2013).
- 63 Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy. Cancer Chemother. Pharmacol. 80(3), 583–589 (2017).
- 64 Alpha emitter radium-223 and survival in metastatic prostate cancer. N. Engl. J. Med. 369(3), 213–223 (2013).
- 65 An exploratory analysis of alkaline phosphatase, lactate dehydrogenase, and prostate-specific antigen dynamics in the Phase 3 ALSYMPCA trial with radium-223. Ann. Oncol. 28(5), 1090–1097 (2017).
- 66 Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm Phase 3b trial. Lancet Oncol. 17(9), 1306–1316 (2016).
- 67 . Survival outcomes of sipuleucel-T Phase III studies: impact of control-arm cross-over to salvage immunotherapy. Cancer Immunol. Res. 3(9), 1063–1069 (2015).
- 68 Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled Phase 3 study. Lancet Oncol. 13(10), 983–992 (2012).
- 69 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 (2016).
- 70 Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled Phase 3 study. Lancet Oncol. 16(2), 152–160 (2015).
- 71 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. BMC Cancer 16, 214 (2016).
- 72 . A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis. Clin. Cancer Res. 13(21), 6396–6403 (2007).
- 73 . Prediction of survival following first-line chemotherapy in men with castration-resistant metastatic prostate cancer. Clin. Cancer Res. 16(1), 203–211 (2010).
- 74 Serum alkaline phosphatase changes predict survival independent of PSA changes in men with castration-resistant prostate cancer and bone metastasis receiving chemotherapy. Urol. Oncol. 30(5), 607–613 (2012).
- 75 Impact of cabazitaxel on 2-year survival and palliation of tumour-related pain in men with metastatic castration-resistant prostate cancer treated in the TROPIC trial. Ann. Oncol. 24(9), 2402–2408 (2013).
- 76 The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer. Eur. J. Cancer 51(17), 2562–2569 (2015).
- 77 Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 363(5), 411–422 (2010).
- 78 Placebo-controlled Phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J. Clin. Oncol. 24(19), 3089–3094 (2006).
- 79 Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur. Urol. 66(5), 815–825 (2014).
- 80 Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 364(21), 1995–2005 (2011).
- 81 Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 13(12), 1210–1217 (2012).
- 82 Abiraterone in metastatic prostate cancer without previous chemotherapy. N. Engl. J. Med. 368(2), 138–148 (2013).
- 83 Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study. Oncotarget 7(26), 40085–40094 (2016).
- 84 Enzalutamide in metastatic prostate cancer before chemotherapy. N. Engl. J. Med. 371(5), 424–433 (2014).
- 85 Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 367(13), 1187–1197 (2012).
- 86 Circulating AR copy number and outcome to enzalutamide in docetaxel-treated metastatic castration-resistant prostate cancer. Oncotarget 7(25), 37839–37845 (2016).
- 87 Prognostic factors and risk stratification in patients with castration-resistant prostate cancer receiving docetaxel-based chemotherapy. BMC Urol. 16, 13 (2016).
- 88 Docetaxel and atrasentan versus docetaxel and placebo for men with advanced castration-resistant prostate cancer (SWOG S0421): a randomised Phase 3 trial. Lancet Oncol. 14(9), 893–900 (2013).
- 89 Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421. J. Natl Cancer Inst. 106(4), dju013 (2014).
- 90 Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351(15), 1513–1520 (2004).
- 91 . Serum alkaline phosphatase differentiates prostate-specific antigen flare from early disease progression after docetaxel chemotherapy in castration-resistant prostate cancer with bone metastasis. J. Cancer Res. Clin. Oncol. 140(10), 1769–1776 (2014).
- 92 Combination of hemoglobin, alkaline phosphatase, and age predicts optimal docetaxel regimen for patients with castration-resistant prostate cancer. Int. J. Clin. Oncol. 19(5), 946–954 (2014).
- 93 Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 376(9747), 1147–1154 (2010).
- 94 Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled Phase II study. Lancet Oncol. 8(7), 587–594 (2007).
- 95 First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin. Cancer Res. 11(12), 4451–4459 (2005).
- 96 A randomized, dose-response, multicenter Phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur. J. Cancer 48(5), 678–686 (2012).
- 97 . 18F-fluoride PET: changes in uptake as a method to assess response in bone metastases from castrate-resistant prostate cancer patients treated with 223Ra-chloride (Alpharadin). EJNMMI Res. 1(1), 4 (2011).
- 98 Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases. Int. J. Clin. Oncol. 22(5), 954–963 (2017).
- 99 . Changes in skeletal tumor activity on 18F-choline PET/CT in patients receiving 223radium radionuclide therapy for metastatic prostate cancer. Nucl. Med. Mol. Imaging 49(2), 160–164 (2015).
- 100 . Evaluation of bone metastases by 18F-choline PET/CT in a patient with castration-resistant prostate cancer treated with radium-223. Urologia 84(1), 61–64 (2017).
- 101 Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a Phase 3, double-blind, randomised trial. Lancet Oncol. 15(7), 738–746 (2014).
- 102 Changes in alkaline phosphatase (ALP) dynamics and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 in an international early access program (EAP). Poster presented at the ESMO Congress, 7–11 October 2016, Copenhagen, Denmark. www.poster-submission.com/esmo2016/visitors/carousel.