Prevalence study of intermittent hormonal therapy of Prostate Cancer patients in Spain

Background: Although intermittent androgen deprivation therapy was introduced many years ago to improve patients’ quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that those patients could be overtreated. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain. Methods: A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants (36.22% of the total population in Spain). We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy (PIAD) overall and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy‐associated medications. Results: A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues (353,162) administered alone or in combination with anti‐androgens (509,843). Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual PIAD along the study was 6.6% in the total population studied, and the overall %IAD during the five‐year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens. Conclusions: An important proportion of prostate cancer patients in Spain could benefit from intermittent androgen therapy during the study period while avoiding overtreatment harms associated with continuous hormonal therapy.

SUN-089 Novel Genetic and Biochemical Findings of DLK1 Deficiency in Children with Central Precocious Puberty - a Collaborative Brazilian-Spanish Study

Background: Delta-like 1 homolog (DLK1), also known as pre-adipocyte factor 1 (Pref-1), is part of the Notch signaling pathway that controls many developmental processes. Loss-of-function mutations of DLK1 have been identified in children with central precocious puberty (CPP), as well as in women who had precocious menarche (≤ 9 years) with an unfavorable metabolic profile. Objective: To investigate genetic and biochemical aspects of DLK1 in a cohort of children with CPP. Patients: A large cohort of Spanish children with idiopathic CPP (Spanish PUBERE Registry) was studied. Genomic DNA was obtained from 444 individuals, including 168 index cases with CPP and their close relatives. Automatic sequencing of the coding region (5 exons) of DLK1 was performed in all index cases. Serum DLK1 levels were measured by using a soluble DLK1 enzyme-linked immunosorbent assay (ELISA). Results: A rare allelic deletion (c.401_404 + 8del) of a splice site junction of DLK1 was identified in a girl with sporadic CPP. Pubertal signs appeared at 5.7 years of age with progressive puberty (basal LH: 1.7 mIU/mL, peak LH: 32.77 mIU/mL; basal FSH: 6.32 mIU/mL, peak FSH: 19.89 mIU/mL), BA/CA 1.7 years; normal cranial MRI). She received LHRH analogues (6.3 - 10.1 years of CA) with no side effects. At 14.9 years of age height and BMI are 152.9 cms and 18 kg/m2, respectively, presenting regular menses. Familial segregation analysis showed that the affected child was the only carrier of this deletion characterizing a de novo mutation (biological paternity and maternity were confirmed by microsatellite analysis). Serum DLK1 levels were undetectable (<0.4 ng/mL) in this girl, supporting that the deletion lead to complete lack of DLK1 production. Her father, mother and sister had normal serum DLK1 levels (ranged 6.36 ng/mL to 8.98 ng/mL). Two rare consecutive nucleotide changes in the promoter region of the DLK1 gene (c.-222 C>A and c.-223 G>A) were also identified in an adopted child with CPP. They are located in a transcription factor binding site for SP1 (a zinc finger transcription factor). Pubertal signs appeared at 6.7 years of age with progressive puberty (Basal LH: 0.5 mIU/mL, peak LH: 15.9 mIU/mL, basal FSH: 1.52 mIU/mL, peak FSH: 6.56 mIU/mL, BA/CA 1.4 years; normal cranial MRI). She is under therapy with LHRH analogues with no side effects. Conclusion: Novel DLK1 findings were identified in the Spanish cohort of children with CPP, reinforcing a significant role of this factor in human pubertal timing.

Intergroup study EORTC-1532-gucg: A phase 2 randomized open-label study of oral darolutamide (ODM-201) vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in men with hormone naive prostate cancer (PCa).

TPS406 Background: Androgen deprivation therapy (ADT) by LHRH analogues aims to lower serum testosterone. ADT is associated with several side effects that include hot flushes, depression, loss of libido, metabolic disturbances leading to an increase risk of cardiovascular disease, increased bone resorption leading to increased risk of osteoporosis and skeletal fracture. AR antagonists may circumvent these side effects by suppressing AR transcription by competitive inhibition of AR, without lowering systemic testosterone. In Europe, first generation AR antagonists bicalutamide 150 mg is registered for the treatment of non-metastatic hormone-naïve PCa. is a novel AR antagonist that is structurally distinct with higher AR-binding affinity compared to bicalutamide, enzalutamide, and apalutamide. The aim of this trial is to investigate the activity, safety and tolerability of darolutamide as single agent, as an alternative to LHRH analogues in men requiring ADT. Methods: EORTC-1532-GUCG (NCT02972060) will randomize 250 men with hormone-naïve PCa 1:1 to 600 mg (2× 300-mg tablets) bid of darolutamide1 or LHRH agonist or antagonist, stratified for type of ADT (agonist vs. antagonist), disease extent (measurable, non-measurable, vs. no metastasis) and age (≥70 vs < 70 years). Key inclusion criteria include histologically confirmed asymptomatic PCa (all stages) for whom continuous ADT is indicated for a minimum period of 24 weeks. Patients with up to 4 confirmed not visceral metastases, are allowed. Baseline total testosterone should be ≥ 8 nmol/L or 230 ng/dL. Primary endpoint is PSA response assessed at 24 weeks, defined as a ≥ 80% decline in PSA at week 24 in the darolutamide study arm. The ADT arm is used as an internal non comparative control. Key secondary endpoints include: Change in hormone-treatment related symptoms scale of the EORTC QLQ-PR25 at 24 weeks (comparison between arms); objective response rate at 24 weeks in patients with measurable disease at baseline, safety according to NCI-CTC version 4.0. Clinical trial information: NCT02972060.

Comparison of serum testosterone levels in prostate cancer patients

Introduction: The prostate secretes enzymes and nutrients to promote sperm motility. Recent reports suggest that the prostate may also secrete testosterone, which is believed to be a fuel for prostate tumour growth. The aim of this study was to determine if a difference in serum testosterone levels exists between men on luteinizing hormone releasing-hormone (LHRH) agonists who have undergone radical prostatectomy, radiation or hormone therapy as primary prostate cancer treatment.Methods: Serum testosterone levels were evaluated in 165 consecutive prostate cancer patients using LHRH analogues for >3 months. We excluded patients receiving either radiation or chemotherapy at time of time of testosterone measurement. Patients were classified based on primary treatment: (1) radical prostatectomy; (2) radiation; or (3) primary hormone therapy. We used one-way ANOVA to compare testosterone levels. Pearson correlation was used to correlate testosterone with prostate-specific antigen (PSA) and time on LHRH agonists. Multivariable linear regression was used to predict serum testosterone levels.Results: The median (interquartile range) serum testosterone levels were 1.4 (1-1.9), 1.3 (1-1.625) and 1.25 (0.9-1.525) nmol/L for radical prostatectomy, radiation and primary hormone therapy groups, respectively. There was no statistically significant difference in testosterone levels between the groups (p = 0.3). No correlation was found between testosterone and PSA levels or time on LHRH (r = 0.02 and r = 0.01), respectively. Multivariable linear regression showed that none of the clinical variables were predictors ofserum testosterone levels.Conclusion: Our study suggests that primary treatment does notaffect serum testosterone levels among men using LHRH analogues.