Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer.

BACKGROUND: We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. METHODS: The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. RESULTS: Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. CONCLUSION: High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.

Randomized, placebo-controlled, phase III trial of sunitinib plus prednisone versus prednisone alone in progressive, metastatic, castration-resistant prostate cancer.

PURPOSE: We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg/d continuously or placebo. Patients also received oral prednisone 5 mg twice daily. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS). Two interim analyses were planned. RESULTS: Overall, 873 patients were randomly assigned to receive sunitinib (n = 584) or placebo (n = 289). The independent data monitoring committee stopped the study for futility after the second interim analysis. After a median overall follow-up of 8.7 months, median OS was 13.1 months and 11.8 months for sunitinib and placebo, respectively (hazard ratio [HR], 0.914; 95% CI, 0.762 to 1.097; stratified log-rank test, P = .168). PFS was significantly improved in the sunitinib arm (median 5.6 v 4.1 months; HR, 0.725; 95% CI, 0.591 to 0.890; stratified log-rank test, P < .001). Toxicity and rates of discontinuations because of adverse events (AEs; 27% v 7%) were greater with sunitinib than placebo. The most common treatment-related grade 3/4 AEs were fatigue (9% v 1%), asthenia (8% v 2%), and hand-foot syndrome (7% v 0%). Frequent treatment-emergent grade 3/4 hematologic abnormalities were lymphopenia (20% v 11%), anemia (9% v 8%), and neutropenia (6% v < 1%). CONCLUSION: The addition of sunitinib to prednisone did not improve OS compared with placebo in docetaxel-refractory mCRPC. The role of antiangiogenic therapy in mCRPC remains investigational.

Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer.

OBJECTIVE: To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons. RESULTS: An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. CONCLUSIONS: Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.