Francisco Gómez Veiga

Prevention of Bone Metastases in Patients with High-risk Nonmetastatic Prostate Cancer Treated with Zoledronic Acid: Efficacy and Safety Results of the Zometa European Study (ZEUS)

BACKGROUND Patients with high-risk localised prostate cancer (PCa) are at risk of developing bone metastases (BMs). Zoledronic acid (ZA) significantly reduces the incidence of skeletal complications in castration-resistant metastatic PCa versus placebo. OBJECTIVE To investigate ZA for the prevention of BMs in high-risk localised PCa. DESIGN, SETTING, AND PARTICIPANTS Randomised open-label multinational study with patients having at least one of the following: prostate-specific antigen ≥20 ng/ml, node-positive disease, or Gleason score 8-10. INTERVENTION Standard PCa therapy alone or combined with 4mg ZA intravenously every 3 mo for ≤4 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS BMs were assessed using locally evaluated bone-imaging procedures (BIPs), with subsequent blinded central review. Patients with BMs, time to BMs, overall survival, and adverse events were compared between treatment groups. RESULTS AND LIMITATIONS A total of 1393 of 1433 randomised patients were used for intention-to-treat (ITT) efficacy analyses, with 1040 patients with BIP-BM outcome status at 4±0.5 yr. The local urologist/radiologist diagnosed BIP-BMs in 88 of 515 patients (17.1%) in the ZA group and 89 of 525 patients (17.0%) in the control group (chi-square test: p=0.95), with a difference between proportions of 0.1% (95% confidence interval [CI], -4.4 to 4.7) in favour of the control group. In the ITT population (n=1393), the Kaplan-Meier estimated proportion of BMs after a median follow-up of 4.8 yr was 14.7% in the ZA group versus 13.2% in the control group (log-rank: p=0.65). Low hot spot numbers on bone scans were confirmed as metastases with additional imaging. Central reviews of BIPs were possible only on a subset of patients. CONCLUSIONS ZA administered every 3 mo was demonstrated to be ineffective for the prevention of BMs in high-risk localised PCa patients at 4 yr. PATIENT SUMMARY Zoledronic acid administered every 3 mo was demonstrated to be ineffective for the prevention of bone metastases in high-risk nonmetastatic PCa patients at 4 yr. TRIAL REGISTRATION The ZEUS trial is registered in the Dutch trial register www.trialregister.nl and the ISRCTN register at http://www.controlled-trials.com/ISRCTN66626762.

Degarelix versus Goserelin (+ Antiandrogen Flare Protection) in the Relief of Lower Urinary Tract Symptoms Secondary to Prostate Cancer: Results from a Phase IIIb Study (NCT00831233)

Introduction: No studies to date have assessed the efficacy/tolerability of degarelix in the relief of lower urinary tract symptoms (LUTS) secondary to prostate cancer (PrCa). Methods: Patients were randomised to degarelix 240/80 mg or goserelin 3.6 mg + bicalutamide flare protection (G+B); both treatments were administered for 3 months. The primary endpoint was change in International Prostate Symptom Score (IPSS) at week 12 compared with baseline. Results: This study was stopped early due to recruitment difficulties. 40 patients received treatment (degarelix n = 27; G+B n = 13); most had locally advanced disease and were highly symptomatic. Degarelix was non-inferior to G+B in reducing IPSS at week 12 in the full analysis set (p = 0.20); the significantly larger IPSS reduction in the per-protocol analysis (p = 0.04) was suggestive of superior reductions with degarelix. Significantly more degarelix patients had improved quality of life (IPSS question) at week 12 (85 vs. 46%; p = 0.01). Mean prostate size reductions at week 12 were 42 versus 25% for patients receiving degarelix versus G+B, respectively (p = 0.04; post hoc analysis). Most adverse events were mild/moderate; more degarelix patients experienced injection site reactions whereas more G+B patients had urinary tract infections/cystitis. Conclusion: In 40 men with predominantly locally advanced PrCa and highly symptomatic LUTS, degarelix was at least non-inferior to G+B in reducing IPSS at week 12.

The Metabolic Syndrome and its Components in Patients with Prostate Cancer on Androgen Deprivation Therapy

PURPOSE Androgen deprivation therapy may promote the development of the metabolic syndrome in patients with prostate cancer. We assessed the prevalence of the full metabolic syndrome and its components during the first year of androgen deprivation therapy. MATERIALS AND METHODS This observational, multicenter, prospective study included 539 patients with prostate cancer scheduled to receive 3-month depot luteinizing hormone-releasing hormone analogs for more than 12 months. Waist circumference, body mass index, lipid profile, blood pressure and fasting glucose were evaluated at baseline and after 6 and 12 months. The metabolic syndrome was assessed according to NCEP ATP III criteria (2001) and 4 other definitions (WHO 1998, AACE 2003, AHA/NHLBI 2005 and IDF 2005). RESULTS At 6 and 12 months after the initiation of androgen deprivation therapy, significant increases were observed in waist circumference, body mass index, fasting glucose, triglycerides, total cholesterol, and high-density and low-density lipoprotein cholesterol. No significant changes in blood pressure 130/85 or greater were detected. A nonsignificant increase of 3.9% in the prevalence of the full metabolic syndrome (ATP III) was observed (22.9% at baseline vs 25.5% and 26.8% at 6 and 12 months, respectively). The prevalence of the metabolic syndrome at baseline varied according to the definition used, ranging from 9.4% (WHO) to 50% (IDF). At 12 months significant increases in prevalence were observed with the WHO (4.1%) and AHA/NHLBI (8.1%) definitions. CONCLUSIONS Androgen deprivation therapy produces significant early effects on waist circumference, body mass index, fasting glucose, triglycerides and cholesterol. The prevalence of and increase in the metabolic syndrome depend on the defining criteria. Counseling patients on the prevention, early detection and treatment of specific metabolic alterations is recommended.

Intermittent Versus Continuous Androgen Deprivation Therapy in Patients with Relapsing or Locally Advanced Prostate Cancer: A Phase 3b Randomised Study (ICELAND)

BACKGROUND Intermittent androgen deprivation (IAD) has received increasing attention; however, the current literature is still limited, especially in nonmetastatic prostate cancer (PCa), and the relative efficacy and safety benefits of IAD versus continuous androgen deprivation (CAD) remain unclear. OBJECTIVE To add to the knowledge base regarding efficacy and potential benefits, including reduced side effects and improved quality of life (QoL), of IAD versus CAD in patients with nonmetastatic relapsing or locally advanced PCa. DESIGN, SETTING, AND PARTICIPANTS A 42-mo phase 3b open-label randomised study in 933 patients from 20 European countries. INTERVENTION Following a 6-mo induction with leuprorelin acetate (Eligard) 22.5mg 3-mo depot, patients were randomised to CAD or IAD with leuprorelin for 36 mo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was time to prostate-specific antigen (PSA) progression while receiving luteinising hormone-releasing hormone agonist, defined as three consecutive increasing PSA values ≥ 4 ng/ml ≥ 2 wk apart. Secondary end points included PSA progression-free survival (PFS), overall survival (OS), testosterone levels, performance status, and QoL. RESULTS AND LIMITATIONS A total of 933 patients entered the induction phase; 701 were randomised. The median number of injections administered after randomisation was 12 (range: 1-12) for the CAD group and 3 (range: 1-10) for the IAD group. There were no statistically significant or clinically relevant differences between the groups for time to PSA progression, PSA PFS, OS, mean PSA levels over time, or QoL. A similar number of adverse events was observed in each group; the most common were hot flushes and hypertension. Study limitations include the open-label design and absence of formal testosterone recovery assessment. CONCLUSIONS IAD and CAD demonstrated similar efficacy, tolerability, and QoL in men with nonmetastatic PCa. The principal benefit of IAD compared with CAD is a potential cost reduction with comparable OS rates. There are no apparent QoL benefits. PATIENT SUMMARY This randomised trial showed that both intermittent and continuous hormone therapy had similar efficacy, tolerability, and quality-of-life profiles in patients with relapsing M0 or locally advanced prostate cancer. Intermittent therapy may be a valid option for selected patients. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT00378690.

Clinical Outcomes and Testosterone Levels Following Continuous Androgen Deprivation in Patients with Relapsing or Locally Advanced Prostate Cancer: A Post Hoc Analysis of the ICELAND Study

Purpose: Lower serum testosterone levels correlate with improved cause specific survival and longer time to progression in year 1 of continuous androgen deprivation in men with prostate cancer. ICELAND was a large European study demonstrating the efficacy of leuprorelin (Eligard®) during continuous androgen deprivation. In this post hoc analysis we investigated serum testosterone levels within year 1 of continuous androgen deprivation to determine survival and time to progression. Materials and Methods: In ICELAND (ClinicalTrials.gov NCT00378690) patients with locally advanced or relapsing nonmetastatic prostate cancer and with prostate specific antigen 1 ng/ml or less following 6‐month induction with leuprorelin 3‐month depot 22.5 mg (plus bicalutamide 50 mg per day for 1 month) were randomized 1:1 to continuous androgen deprivation (361) or intermittent androgen deprivation (340) with leuprorelin for 36 months. Patients receiving continuous androgen deprivation were stratified by minimum, median and maximum testosterone levels during year 1 of therapy into 20 or less, greater than 20 to 50 and greater than 50 ng/dl subgroups. Cause specific survival and time to prostate specific antigen (castrate resistant prostate cancer) progression were analyzed. Results: A total of 90.1%, 83.5% and 74.5% of patients receiving continuous androgen deprivation achieved minimum, median and maximum serum testosterone levels of 20 ng/dl or less, respectively. Cause specific survival rates and time to prostate specific antigen progression did not differ among the testosterone subgroups. Conclusions: In patients receiving continuous androgen deprivation cause specific survival and time to prostate specific antigen progression did not differ according to testosterone levels in year 1 of therapy. This finding may in part be due to the induction period and the effectiveness of leuprorelin in lowering testosterone.

PD71-08 ANDROGEN RECEPTOR SPLICE VARIANT 7 (AR-V7) IN PATIENTS WITH LOCAL ADVANCED, METASTATIC AND CRPCM: A NOVEL CAPILLARY NANO-INMUNOASSAY TECHNIQUE

INTRODUCTION AND OBJECTIVES: Docetaxel or cabazitaxel-based chemotherapy continues to have a critical role in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). However, responses are heterogeneous and resistance to therapy is a pressing clinical problem. With the goal of developing liquid biomarkers to aid in treatment selection, we sought to identify genes associated with resistance to chemotherapy using a circulating tumor cell (CTC)-based approach. METHODS: Whole blood (~5mL) was obtained from 25 patients with mCRPC starting docetaxel (n1⁄421) or cabazitaxel (n1⁄44). CTCs were isolated using anti-EpCAM-conjugated magnetic beads, and following cell lysis, mRNA was extracted followed by multiplex qRTPCR for 44 prostate cancer-related genes plus internal controls. Gene expression was normalized to controls, and samples were considered CTC-positive based on a previously established set of epithelial markers (EpCAM, EGFR, DSG2, KRT8, KRT18 and KRT19). The primary endpoint was PSA progression-free survival (PFS), with PSA progression defined as an increase of 25% or more above the nadir. Univariable Cox regression analyses were performed to assess for genes associated with PFS at false discovery rate (FDR) < 0.20. RESULTS: Among 25 patients with mCRPC, we identified 84% (21/25) with detectable CTCs. The median age of the cohort was 62 years (IQR 58-70). At a median (IQR) follow up of 5.4 (3.4-9.3) months, 47.6 % (10/21) of patients showed a PSA decrease of at least 30% following treatment initiation. 18/21 patients (85.7%) experienced PSA progression at a median of 2.8 months (IQR 1.7-4.8). In the Cox analysis, KLK2 (HR 2.54, 95%CI 1.24-5.21, p1⁄40.011), GAS6 (HR 3.50, 95% CI 1.30-9.42, p1⁄40.013), and BMP7 (HR 2.01, 95%CI 1.15-3.52; p1⁄40.014) were associated with shorter PFS. CONCLUSIONS: Wehave identified three genes associatedwith progression in mCRPC patients initiating chemotherapy. While these early results need further confirmation, they suggest that CTCs may be utilized to help guide precision-based treatment strategies in patients with mCRPC. Additionally, these results corroborate our recent in vitro and in vivo findings (Lee et al, J Cell Biochem, 2016) indicating that GAS6 protects prostate cancer cells from docetaxel-induced apoptosis.