Developing prognostic models for advanced prostate cancer when the goal line keeps changing
Authors: S.Y.F. Fu, K.N. Chi
Journal: Annals of Oncology (2018)

The treatment landscape of metastatic castration-resistant prostate cancer (mCRPC) has changed rapidly over the last decade with the availability of six life-prolonging therapies. Multiple prognostic models have been developed to risk-stratify patients in the modern treatment era (Table 1) [1.Halabi S. Lin C.-Y. Small E.J. et al.Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy.J Natl Cancer Inst. 2013; 105: 1729-1737Crossref PubMed Scopus (111) Google Scholar, 2.Halabi S. Lin C.-Y. Kelly W.K. et al.Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer.J Clin Oncol. 2014; 32: 671-677Crossref PubMed Scopus (287) Google Scholar, 3.Chi K.N. Kheoh T. Ryan C.J. et al.A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.Ann Oncol. 2016; 27: 454-460Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 4.Ryan C.J. Kheoh T. Li J. et al.Prognostic index model for progression-free survival in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with abiraterone acetate plus prednisone.Clin Genitourin Cancer. 2018; 16: 72-77.e1Abstract Full Text Full Text PDF Scopus (17) Google Scholar, 5.Armstrong A.J. Lin P. Higano C.S. et al.Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.Ann Oncol. 2018; 29: 2200-2207Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. In this issue ofAnnals of Oncology, Armstrong et al. [5.Armstrong A.J. Lin P. Higano C.S. et al.Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.Ann Oncol. 2018; 29: 2200-2207Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] added to the range of contemporary prognostic models for mCRPC using data collected from the PREVAIL (a phase III, multinational, double-blind, randomised contorlled trial comparing enzalutamide with placebo) trial, which compared enzalutamide with placebo in chemotherapy-naive patients with mCRPC. The internally validated prognostic model contains 11 recognized prognostic variables, including number of bone metastases, liver metastases, presence of pain, alkaline phosphatase, neutrophil-to-lymphocyte ratio (NLR), lactate dehydrogenase, treatment with enzalutamide, albumin, time since diagnosis, haemoglobin, and prostate-specific antigen. A risk score was calculated using regression coefficients from a training set for the 11 variables and a nomogram produced. The model provided a significant separation in the estimated overall survival for patients grouped by median risk score [for low-risk versus high-risk patients the hazard ratio (HR) was 0.35 (95% confidence interval (CI) 0.27–0.46)] as well as based on risk score tertiles [HR for low- and intermediate-risk groups versus high-risk group were 0.20 (95% CI 0.14–0.29) and 0.40 (95% CI 0.30–0.53), respectively]. Predictive biomarkers for enzalutamide efficacy were not identified.Table 1Selected contemporary prognostic models developed for metastatic castration-resistant prostate cancer patientsHalabi et al. [1.Halabi S. Lin C.-Y. Small E.J. et al.Prognostic model predicting metastatic castration-resistant prostate cancer survival in men treated with second-line chemotherapy.J Natl Cancer Inst. 2013; 105: 1729-1737Crossref PubMed Scopus (111) Google Scholar]Halabi et al. [2.Halabi S. Lin C.-Y. Kelly W.K. et al.Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer.J Clin Oncol. 2014; 32: 671-677Crossref PubMed Scopus (287) Google Scholar]Chi et al. [3.Chi K.N. Kheoh T. Ryan C.J. et al.A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.Ann Oncol. 2016; 27: 454-460Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar]Ryan et al. [4.Ryan C.J. Kheoh T. Li J. et al.Prognostic index model for progression-free survival in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with abiraterone acetate plus prednisone.Clin Genitourin Cancer. 2018; 16: 72-77.e1Abstract Full Text Full Text PDF Scopus (17) Google Scholar]Armstrong et al. [5.Armstrong A.J. Lin P. Higano C.S. et al.Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer.Ann Oncol. 2018; 29: 2200-2207Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]Population/treatmentCabazitaxel (TROPIC)Docetaxel (CALGB 90401)Abiraterone (post-chemotherapy)Abiraterone (chemotherapy-naive)Enzalutamide (chemotherapy-naive)Prognosis assessedOverall survivalOverall survivalOverall survivalProgression-free survivalOverall survivalNumber of Prognostic factors986511Predictive accuracytAUC: 0.73tAUC: 0.73C-index: 0.7C-index: 0.83tAUC: 0.74Variables included in the model Patient status variablesPerformance statusXXXPain/opioid useXXXTrial treatmentX Laboratory variablesHaemoglobinXXXXPSAXXXXALPXXXXLDHXXXXAlbuminXXXNLRX Disease distribution variablesLiver met/visceral metXXXX>10 Bone metXXPresence of nodal metXMeasurable diseaseX Time variablesTime since diagnosisXTime since first-line docetaxelXADT to trial treatmentXXPSA, prostate specific antigen; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio; ADT, androgen-deprivation therapy; tAUC, time-dependent area under the curve. Open table in a new tab PSA, prostate specific antigen; ALP, alkaline phosphatase; LDH, lactate dehydrogenase; NLR, neutrophil-to-lymphocyte ratio; ADT, androgen-deprivation therapy; tAUC, time-dependent area under the curve. The authors are to be commended for their efforts to construct the first prognostic model for chemotherapy-naive mCRPC patients treated with enzalutamide. The model demonstrated a high predictive accuracy for overall survival. It achieves a time-dependent area under the curve of 0.74 which is comparable to other contemporary prognostic models. The prognostic model uses variables that are routinely available in the standard clinical setting, including NLR. NLR reflects systemic inflammation which is recognised as a hallmark of cancer [6.Hanahan D. Weinberg RA. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (34704) Google Scholar]. While the cut-off value for NLR in mCRPC has yet to be defined and varies between 2 and 5 in different studies, an elevated NLR has been shown to be an independent poor prognostic factor [7.Tang L. Li X. Wang B. et al.Prognostic value of neutrophil-to-lymphocyte ratio in localized and advanced prostate cancer: a systematic review and meta-analysis.PLoS One. 2016; 11: 1-13Crossref Scopus (45) Google Scholar,8.Yin X. Xiao Y. Li F. et al.Prognostic role of neutrophil-to-lymphocyte ratio in prostate cancer: a systematic review and meta-analysis.Medicine (Baltimore). 2016; 95: e2544.Crossref PubMed Scopus (43) Google Scholar]. The prognostic value of NLR has been increasingly recognised in various malignancies [9.Templeton A.J. McNamara M.G. Šeruga B. et al.Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis.J Natl Cancer Inst. 2014; 106: dju124Crossref PubMed Scopus (1325) Google Scholar], as well as in mCRPC patients treated with chemotherapy or androgen receptor (AR)-targeted therapies [10.Leibowitz-Amit R. Templeton A.J. Omlin A. et al.Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.Ann Oncol. 2014; 25: 657-662Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 11.Lorente D. Mateo J. Templeton A.J. et al.Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use.Ann Oncol. 2015; 26: 750-755Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 12.Conteduca V. Crabb S.J. Jones R.J. et al.Persistent neutrophil to lymphocyte ratio >3 during treatment with enzalutamide and clinical outcome in patients with castration-resistant prostate cancer.PLoS One. 2016; 11: 1-12Crossref Scopus (34) Google Scholar, 13.Belderbos B.P.S. de Wit R. de Hoop E.O. et al.Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel.Oncotarget. 2017; 8: 106468-106474Crossref PubMed Scopus (9) Google Scholar, 14.Buttigliero C. Pisano C. Tucci M. et al.Prognostic impact of pretreatment neutrophil-to-lymphocyte ratio in castration-resistant prostate cancer patients treated with first-line docetaxel.Acta Oncol (Madr). 2017; 56: 555-562Crossref Scopus (18) Google Scholar]. This is the first time NLR is incorporated in a major prognostic model in mCRPC, and future prognostic model design should continue to assess NLR as a potential prognostic variable. A limitation of the model development is that trial data was used in both training and validation sets. External validation, particularly with real world patients, is needed before generalization to wider patient populations. Although prognostic models can be useful for stratification in clinical trials, the relevance for routine practise is debatable. Knowledge of a patient’s adverse prognosis may encourage closer follow-up, prompt earlier introduction of next line of life-prolonging therapy, or trial participation in search for a potentially more effective therapy. However, the lack of predictive discrimination to assist in treatment selection limits their clinical utility. Recently, molecular biomarkers have been identified that have the potential for adding prognostic and predictive value including circulating tumour cell expression of AR-v7, high levels of circulating tumour DNA, and various genomic alterations including those involvingTP53,AR, the PI3K/AKT pathway and homologous recombination repair [15.Annala M. Vandekerkhove G. Khalaf D. et al.Circulating tumor DNA genomics correlate with resistance to abiraterone and enzalutamide in prostate cancer.Cancer Discov. 2018; 8: 444-457Crossref PubMed Scopus (180) Google Scholar, 16.Wyatt A.W. Azad A.A. Volik S.V. et al.Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer.JAMA Oncol. 2016; 2: 1598-1606Crossref PubMed Scopus (190) Google Scholar, 17.Antonarakis E.S. Lu C. Wang H. et al.AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer.N Engl J Med. 2014; 371: 1028-1038Crossref PubMed Scopus (1635) Google Scholar, 18.Robinson D. Van Allen E.M. Wu Y.M. et al.Integrative clinical genomics of advanced prostate cancer.Cell. 2015; 161: 1215-1228Abstract Full Text Full Text PDF PubMed Scopus (1570) Google Scholar]. Their inclusion with conventional clinical factors in future models may enhance accuracy and provide clinical utility for predicting outcomes. The standard treatment of advanced prostate cancer has been rapidly evolving. Docetaxel was initially approved for mCRPC but now has proven efficacy for patients with metastatic castration sensitive disease [19.Sweeney C.J. Chen Y.-H. Carducci M. et al.Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015; 373: 737-746Crossref PubMed Scopus (1379) Google Scholar]. The novel AR-targeted therapies (abiraterone, enzalutamide, apalutamide) were first introduced for patients after docetaxel, but in short order, their efficacy subsequently demonstrated in chemotherapy-naive patients, then metastatic castration-sensitive disease and most recently for patients with non-metastatic CRPC [20.Fizazi K. Tran N. Fein L. et al.Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer.N Engl J Med. 2017; 377: 352-360Crossref PubMed Scopus (901) Google Scholar, 21.Hussain M. Fizazi K. Saad F. et al.Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer.N Engl J Med. 2018; 378: 2465-2474Crossref PubMed Scopus (429) Google Scholar, 22.Smith M.R. Saad F. Chowdhury S. et al.Apalutamide treatment and metastasis-free survival in prostate cancer.N Engl J Med. 2018; 378: 1408-1418Crossref PubMed Scopus (530) Google Scholar]. This evolution of care limits the applicability of prognostic models developed around a different clinical situation and treatment context, making the current prognostic models for mCRPC obsolete. The development of up-to-date prognostic models is being outpaced by the continued advances in molecular profiling of the disease and the successes of practise changing trials for patients with advanced prostate cancer – this is a good problem for us to have. None declared.