DiPaola, Robert S.

PURPOSE Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo ( Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

AbstractBackgroundE3805 (CHAARTED) is a phase 3 trial demonstrating improved survival for men with metastatic hormone‐sensitive prostate cancer (mHSPC) randomized to treatment with docetaxel (D) and androgen‐deprivation therapy (ADT) versus ADT alone. We assessed the association of baseline body mass index (BMI) and metformin exposure with quality of life (QOL) and prostate cancer outcomes including survival in patients enrolled in the CHAARTED study.MethodsWe performed a posthoc exploratory analysis of the CHAARTED trial of men with mHSPC randomized to treatment with ADT with or without D between 2006 and 2012. Cox proportional hazards models and Kruskal–Wallis test were used to evaluate the association between BMI with QOL and prostate cancer outcomes and between metformin exposure and survival.ResultsIn 788 of 790 enrolled patients with prospectively recorded baseline BMI and metformin exposure status, lower BMI was not associated with survival, but was associated with high volume disease (p < 0.0001) and poorer baseline QOL on functional assessment of cancer therapy–prostate (p = 0.008). Only 68 patients had prevalent metformin exposure at baseline in the CHAARTED trial. Four groups were identified: ADT + D + metformin (n = 39); ADT + D (n = 357); ADT + metformin (n = 29); and ADT alone (n = 363). Baseline clinicopathologic characteristics were similar between groups. In this small exploratory multivariable analysis, metformin exposure was not associated with survival (hazard ratio: 1.15; 95% confidence interval: 0.81–1.63, p = 0.44).ConclusionsThere was no link between baseline BMI and survival, but lower baseline BMI was associated with features of greater cancer burden and poorer QOL.

149 Background: Patients with metastatic hormone-sensitive prostate cancer (mHSPC) have a variable response to ADT and some benefit from the addition of docetaxel or an androgen signaling pathway inhibitor. We found that loss of the epigenetic regulator KDM5D is associated with more aggressive prostate cancer (PC). We sought to determine whether MYBL2 which is regulated by KDM5D mediates this effect. MYBL2 is a transcription factor which controls key genes (e.g. FOXM1) and increases cell cycle progression and survival. Methods: AR expressing hormone-sensitive cell lines, LNCaP and LAPC4 were used. Motif analysis and CHiPseq of LNCaP with and without siKDM5D was performed and impact of modulation of KDM5D and MYBL2 in both cells on cell survival was assessed. Gene expression profiling (GEP) data assessed MYBL2’s association with KDM5D levels in localized disease (publicly available data) and mHSPC (Decipher whole Affymetrix platform on CHAARTED samples). Results: Silencing KDM5D increased H3K4me3 and increased MYBL2 expression. GEP showed a strong negative correlation between KDM5D and MYBL2 in patients with localized PC (-0.66; TCGA) but not from primary prostate cancer tissue with mHSPC (-0.03; CHAARTED). Cells with low KDM5D and high MYBL2 were androgen independent and more resistant to docetaxel. In TCGA, patients with high MYBL2 had a higher rate of relapse from localized disease. In patients with metastatic disease (CHAARTED) low MYBL2 was associated with a better overall survival (OS) on multivariable analysis when treated with ADT or ADT + docetaxel. Conclusions: Low MYBL2 is associated with a longer OS with ADT alone and ADT and docetaxel independent of clinical variables. Patients with high MYBL2 expression had better OS with ADT plus docetaxel compared with patients with high MYBL2 treated with ADT alone.[Table: see text]

4502 Background: Patients with no evidence of disease (NED) after metastasectomy for metastatic renal cell carcinoma (mRCC) are at high risk of recurrence, but no systemic therapy has been shown to benefit this population. Pazopanib is an inhibitor of VEGFR and other kinases that improves progression-free survival in patients with measurable RCC metastatic disease. We performed a randomized, double-blind, placebo-controlled multicenter study to test the hypothesis that pazopanib would improve disease-free survival in patients with mRCC rendered NED after metastasectomy Methods: Patients with NED following metastasectomy were randomized 1:1 to receive pazopanib starting at 800 mg daily vs. placebo for 52 weeks. Patients were stratified by 1 vs. > 1 site of resected disease, and by disease-free interval ≤ vs. > 1 year. Clinical assessment for toxicity and patient-reported outcomes were performed every 4 weeks, and restaging scans every 12 weeks. The study was designed to observe a 42% improvement in disease-free survival (DFS) from 25% to 45% at 3 years. Results: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events had been observed (92% information). The median follow-up from randomization was 30 months (range 0.4 – 66.5 months). The study did not meet the primary endpoint: hazard ratio (95% CI) for DFS was 0.85 (0.55, 1.31) p= 0.47 in favor of pazopanib. At the time of unblinding, 22/129 (17%) of subjects had died. The HR for overall survival (OS) was 2.65 (1.02, 6.9) in favor of placebo ( p= 0.05). Patient-reported outcomes and laboratory correlates will be reported separately. Conclusions: 52 weeks of pazopanib did not improve DFS compared to blinded placebo in patients with mRCC who were NED after metastasectomy. There was a trend toward worse overall survival with pazopanib. Clinical trial information: NCT01575548.

Background: Eribulin mesylate, a synthetic analog of halichondrin B, is a novel tubulin-binding agent that inhibits cancer cell proliferation at low-nanomolar levels. Methods: In a multicenter ECOG trial, patients with progressive metastatic CRPC, ECOG 0-2 were treated with eribulin 1.4 mg/m2 as an IV bolus over 5 minutes on days 1 and 8 of a 21-day cycle. This noncomparative study stratified points to either a chemonaive (CN), prior-taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 40% versus 20% (90% power, one-sided α=0.10) for the CN stratum and 25% versus. 10% (power 87%, one-sided α=0.10) for the Tax and TCx strata. Results: In total, 119 pts received treatment of which 116 were eligible for the primary response determination in this study. Median age 70 years (range, 45 to 88); median number of treatment cycles 4 (range, 1 to 20+); ECOG 0-1 90%. Confirmed PSA response rates (50% decline from baseline) were 29% (90% [18.2%, 41.2%]; P=0.20), 10% (90% [5.2%, 27.1%]; P=1.00), and 4% ([0.2%, 18.3%]; P=0.59) in the chemonaive stratum, the prior-taxane stratum, and the 2-prior-chemotherapy stratum, respectively. Median progression-free survival was 3.5 months (95% CI, 2.0, 5.9), 2.3 months (95% CI, 2.0, 2.9) and 3.7 months (95% CI, 2.1, 4.2) for the chemonaive stratum, the prior-taxane stratum and the 2-prior-chemotherapy stratum, respectively. Nonhematological toxicities of any grade (mainly grade 1 and 2) were fatigue (74%), neuropathy (40%), alopecia (39%), nausea (35%), and anorexia (34%). Common hematological toxicities were decreased leukocytes (75%), decreased neutrophils (72%), and decreased hemoglobin (66%). The most common grade ≥ 3 toxicities were decreased neutrophils (55%), decreased leukocytes (42%), sensory neuropathy (13%), and fatigue (11%). Overall, there was a 4% rate of febrile neutropenia. Conclusions: In summary, per the prespecified study endpoints, eribulin did not have adequate activity in chemotherapy naïve or chemotherapy pretreated patients with metastatic CRPC to support further study in this setting.