Sweeney, Christopher J.

PURPOSE The combination of gemcitabine and cisplatin (GC) is a standard therapy for metastatic urothelial carcinoma. Based on data that angiogenesis plays a role in urothelial carcinoma growth and progression, a randomized placebo-controlled trial was performed with the primary objective of testing whether patients treated with GC and bevacizumab (GCB) have superior overall survival (OS) than patients treated with GC and placebo (GCP). PATIENTS AND METHODS Between July 2009 and December 2014, 506 patients with metastatic urothelial carcinoma without prior chemotherapy for metastatic disease and no neoadjuvant or adjuvant chemotherapy within 12 months were randomly assigned to receive either GCB or GCP. The primary end point was OS, with secondary end points of progression-free survival, objective response, and toxicity. RESULTS With a median follow-up of 76.3 months among alive patients, the median OS was 14.5 months for patients treated with GCB and 14.3 months for patients treated with GCP (hazard ratio for death = 0.87; 95% CI, 0.72 to 1.05; two-sided stratified log-rank P = .14). The median progression-free survival was 8.0 months for GCB and 6.7 months for GCP (hazard ratio = 0.77; 95% CI, 0.63 to 0.95; P = .016). The proportion of patients with grade 3 or greater adverse events did not differ significantly between both arms, although increased bevacizumab-related toxicities such as hypertension and proteinuria occurred in the bevacizumab-treated arm. CONCLUSION The addition of bevacizumab to GC did not result in improved OS. The observed median OS of about 14 months is consistent with prior phase III trials of cisplatin-based chemotherapy.

Abstract VEGF blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLT), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab, and paclitaxel in patients with refractory cancers. The study had a “3 + 3” design, using paclitaxel 80 mg/m2 every week for 3 weeks, in every 4 week cycles, bevacizumab 5 mg/kg every 2 weeks, and sorafenib 200 or 400 mg twice a day, 5 or 7 days/week (5/7, 7/7). The MTD cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg twice a day 5/7, 200 mg twice a day 7/7, and 400 mg twice a day 5/7. DLTs were grade 3 neutropenia >7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand–foot skin reaction (HFSR; cohort 3, 2). MTD was sorafenib 200 mg twice a day 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay >7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia >7 days (1). RP2D was sorafenib 200 mg twice a day 5/7. Most patients (62%) dose reduced sorafenib to 200 mg daily 5/7 after a median 3 (range, 2–17) cycles. Response rates were 48% overall (27) and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival versus alternative genotypes (7 vs. 22 months). Intermittent, low-dose sorafenib (200 mg twice a day 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in patients with refractory cancer (NCT00572078).

30 Background: BM in patients (pts) with CRPC are associated with shorter overall survival (OS) and higher costs. BRI zoledronic acid and denosumab are frequently used to prevent skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line therapy for men with metastatic CRPC. We aimed to assess the impact of BRI on OS and time to first SRE (ttSRE) of pts receiving 1st line treatment AA for CRPC with BM. Methods: A retrospective cohort of pts starting AA as 1st line therapy for CRPC with BM between 2013-2016 was identified through 8 hospitals’ IRB approved registries. Pts were classified by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. Kaplan-Meier method and Cox models were used to assess OS and ttSRE with hazard ratio (HR) estimates (95% CI). Results: Of the 745 pts included (543 deaths), 529 (71.0%) had AA alone and 216 (29.0%) AA+BRI. Median follow-up was 23.5 months. Pts receiving concomitant BRI showed a significantly longer OS and a 35% reduced risk of death compared to AA alone (HR=0.65; 95% CI, 0.54-0.79; P<.0001). The OS benefit with BRI was greater for the subgroup with high volume disease (HV) (HR=0.51; 95% CI, 0.38-0.68; P<.0001). The cohort with AA+BRI had a significantly shorter ttSRE (HR=1.27; 95% CI; 1.0-1.60; P=.0439) and, notably, the risk of first SRE was more than doubled for the subgroup with LV (HR=2.29; 95% CI, 1.57-3.35; P<.0001). On MVA, BRI vs. no BRI, prior local therapy (PLT) vs. no PLT, LV vs. HV, baseline VAS pain ≤3 vs. >5, PS 0 vs. ≥1, and PSA are independently associated with longer OS. Conclusions: The addition of BRI to 1st line AA for CRPC men with BM was associated with improved OS, particularly in HV, and worsened ttSRE, more evident in LV. These data suggest a potentially different impact of concomitant BRI on HV vs. LV, which could affect clinical decision making.[Table: see text]

174 Background: Docetaxel (D) and cabazitaxel (C) are standard chemotherapies for mCRPC. A reliable biomarker predictive of resistance to D or C is yet to be identified. We aimed to assess the association between genetic amplification of the multidrug resistance transporter ABCB1 (ABCB1 amp) and primary resistance (RES) to D or C for mCRPC, using cfDNA. Methods: A cohort (A) of 136 patients (pts) with at least 1 plasma sample drawn and stored within 1 year prior to starting D for mCRPC (2002-2014) and a cohort (B) of 42 pts with at least 1 plasma sample from within 1 year prior to starting C for mCRPC (2010-2016) were identified from the Dana-Farber Cancer Institute IRB approved database. Whole genome sequencing (WGS) at 0.1x coverage, termed ultra-low pass WGS (ULP-WGS), was performed on cfDNA extracted from the selected samples (1000μL/subject) and sequencing data were analyzed using a tool called ichorCNA to identify cases with sufficient tumor DNA content (>7%) for accurate detection of copy number alterations (CNAs) including ABCB1 amp. Primary objective was the association between ABCB1 amp and RES to D or C. RES was defined as lack of response (no PSA50 decline or radiologic response per RECIST criteria 1.1, within 4 months from treatment start). Odds ratio (OR) was used to compare odds of RES to D or C for pts with ABCB1 amp and P-values were calculated by Fisher’s exact test. Results: Of the selected 178 pts, 66 had tumor fraction >7%: 45 pts in cohort A and 21 in cohort B. No significant association was noted between ABCB1 amp and RES to D (P=0.7123; OR=1.600) or C (P=1.000; OR=1.0606). RES was observed in 26 pts (57.8%) of cohort A and 18 (85.7%) of cohort B. ABCB1 amp was found in 9 pts (20%; 95% CI, 9.6-34.6) in group A and 6 of them (66%) had RES to D. ABCB1 amp rate among D-resistant men was 23.1% (95% CI, 9.0-43.7). In group B, 2 pts (9.5%; 95% CI, 1.2-30.4) had ABCB1 amp and both of them had RES to C. ABCB1 rate among C-resistant pts was 11.1% (95% CI, 1.4-34.7). Conclusions: In this study, ABCB1 amp using cfDNA did not show statistically significant correlation with RES to D or C for pts with mCRPC. Future studies including ABCB1 amp in a suite of putative biomarkers and larger sample size may aid drawing definitive conclusions.

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]

e16508 Background: BM in patients (pts) with CRPC correlate with higher mortality and costs. BRI zoledronic acid and denosumab are frequently used for the prevention of skeletal-related events (SRE) in pts with CRPC and BM. AA is the most common 1st line treatment for men with metastatic CRPC. We sought to evaluate the impact of BRI on time to first SRE (ttSRE) and OS of pts receiving 1st line therapy AA for CRPC with BM. Methods: We identified a cohort of men starting AA as 1st line therapy for CRPC with BM between 2013-2015 from 7 hospitals’ IRB approved registries. Pts were grouped by use of concomitant BRI and subgrouped by volume of disease (per E3805 definition) at AA start. The endpoints were OS, defined as time from AA start to death or last follow-up visit, and ttSRE. Results: Of the 338 pts included, 256 (76%) received AA alone and 82 (24%) AA+BRI. ECOG PS (PS) was ≥1 for 178 pts (52.7%). No statistically significant difference in ttSRE was found between the 2 cohorts [see Table]. Median follow-up for OS was 25.6 months. Pts receiving concomitant BRI showed a significantly longer OS and a 36% decreased risk of death compared to AA alone (HR = 0.64; 95% CI, 0.64 0.46-0.91; p = 0.012). Notably, OS in the AA alone group was shorter than commonly described. The OS benefit with BRI was greater for men with high volume disease (HV) (HR = 0.42; 95% CI, 0.25-0.71; p = 0.001). On MVA, BRI vs. no BRI, low volume of disease vs. HV, PS 0 vs. ≥1, baseline VAS pain ≤3 vs. > 5, and baseline PSA are independently associated with longer OS. Conclusions: Using a multicenter database, the addition of BRI to 1st line AA for CRPC men with BM and poor prognostic factors did not improve prevention of SRE. However, concomitant use of BRI and AA was associated with a significantly improved OS, particularly in HV. Further research to determine the driving factors is needed. [Table: see text]

Abstract Introduction: Epidemiologic data support an inverse association between statin use and risk of lethal prostate cancer, but contributing mechanisms have not been elucidated. Herein, using data from the Health Professionals Follow-up Study (HPFS), we updated our previous analysis of statins and lethal prostate cancer with a decade of additional follow-up, and incorporated immunohistochemistry (IHC)-based biomarkers and gene expression profiling to identify putative molecular mechanisms contributing to the association. Methods: We included data from 44,076 HPFS participants who were cancer free in 1990, with follow-up through 2012. Participants reported prediagnostic statin use on biennial questionnaires. Statin use was categorized as current vs. never/past use, with current users further categorized as long-term vs. short-term users (≥6 vs. &lt;6 years). To classify prostate cancer molecular subtypes, genetically validated IHC assays for TMPRSS2:ERG fusion and PTEN loss were conducted on tissue microarrays for 891 and 660 cases, respectively. Whole-genome mRNA profiling of tumor and adjacent normal tissue was completed for 237 and 114 cases, respectively, using Affymetrix GeneChip Human Gene 1.0 ST arrays. We used Cox proportional hazards analysis to generate hazard ratios (HR) and 95% confidence intervals (CI) for associations between statin use and risk of overall, advanced (stage T3b or higher at diagnosis, metastatic or fatal), and lethal (metastatic or fatal) prostate cancer, as well as molecular subtypes, adjusted for PSA testing behavior and potential confounders including obesity and smoking. Moreover, we explored gene expression pathways in tumor and adjacent normal prostate tissue of statin users vs. nonusers using gene set enrichment analysis (GSEA). Results: During 22 years of follow-up, 6,144 men were diagnosed with prostate cancer; 1,051 (17%) had advanced disease and 827 (13%) developed lethal prostate cancer. Of cases with molecular subtype available, 48% were ERG-positive and 14% PTEN-null. In multivariable analysis, relative to never/past use, current statin use was inversely associated with risk of advanced (HR 0.84; 95% CI 0.68-1.04) and lethal (HR 0.78; 95% CI 0.68-1.01) prostate cancer. These associations were more pronounced in long-term users, where ≥6 years of prediagnosis statin use was significantly associated with a lower risk of advanced (HR 0.72; 95% CI 0.53-0.97) and lethal prostate cancer (HR 0.64; 95% CI 0.45-0.92), relative to nonuse. Long-term statin use was not associated with overall prostate cancer risk, whether ERG-positive (HR 0.89; 95% CI 0.59-1.35) or ERG-negative (HR 1.06; 95% CI 0.74-1.50). However, relative to nonuse, a longer duration of prediagnosis statin use was associated with reduced risk of PTEN-null cancers (HR 0.42; 95% CI 0.20-0.90), but not PTEN-intact disease (HR 1.18; 95% CI 0.95-1.46; p-heterogeneity=0.01). In GSEA, we identified T cell, B cell, and phosphatidylinositol (PI3K) signaling among the top pathways enriched in tumor-adjacent normal prostate tissue of current statin users, relative to never users. Intriguingly, no gene sets were differentially expressed by statin use in the tumor. Discussion: Our updated findings from the HPFS are consistent with our prior findings and other epidemiologic data supporting a role for statins in lethal prostate cancer prevention. Molecular classification of tumors identified PTEN/PI3K signaling and inflammation/immune activation as two potential mechanisms contributing to this association. Elucidating molecular mechanisms mediating the association between statin use and lower risk of lethal prostate cancer will provide support for a causal effect of statins on lethal prostate cancer risk and could inform statin clinical trials with appropriate intermediate endpoints. Citation Format: Emma H. Allott, Ericka M. Ebot, Amparo G. Gonzalez-Feliciano, Sarah C. Markt, Kathryn M. Wilson, Thomas U. Ahearn, Travis A. Gerke, Mary K. Downer, Konrad H. Stopsack, Jennifer R. Rider, Stephen J. Freedland, Elizabeth A. Platz, Meir J. Stampfer, Edward L. Giovannucci, Christopher J. Sweeney, Stephen P. Finn, Lorelei A. Mucci. Molecular tumor profiling to identify mechanisms linking statin use with lower risk of lethal prostate cancer: Results from the Health Professionals Follow-up Study [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A015.

Abstract Background: Inflammation is linked to prostate cancer progression and is mediated by NF-κB. Tristetraprolin is a key node of NF-κB activation and we investigated its biological and prognostic role in lethal prostate cancer. Methods: In vitro assays assessed the function of tristetraprolin and the association between low mRNA tristetraprolin levels and lethal prostate cancer (metastatic disease or death) was assessed across independent prostatectomy cohorts: (i) nested case-control studies from Health Professionals Follow-up Study and Physicians’ Health Study, and (ii) prostatectomy samples from Cleveland Clinic, Mayo Clinic, Johns Hopkins and Memorial Sloan Kettering Cancer Center. Tristetraprolin expression levels in prostatectomy samples from patients with localized disease and biopsies of metastatic castration–resistant prostate cancer (mCRPC) were assessed in a Cornell University cohort. Results: In vitro tristetraprolin expression was inversely associated with NF-κB–controlled genes, proliferation, and enzalutamide sensitivity. Men with localized prostate cancer and lower quartile of tumor tristetraprolin expression had a significant, nearly two-fold higher risk of lethal prostate cancer after adjusting for known clinical and histologic prognostic features (age, RP Gleason score, T-stage). Tristetraprolin expression was also significantly lower in mCRPC compared with localized prostate cancer. Conclusions: Lower levels of tristetraprolin in human prostate cancer prostatectomy tissue are associated with more aggressive prostate cancer and may serve as an actionable prognostic and predictive biomarker. Impact: There is a clear need for improved biomarkers to identify patients with localized prostate cancer in need of treatment intensification, such as adjuvant testosterone suppression, or treatment de-intensification, such as active surveillance. Tristetraprolin levels may serve as informative biomarkers in localized prostate cancer.