Therapy In Men Research Articles

Evaluating Sperm Recovery Time and Efficacy of Monotherapy vs. Combination Therapies in Men with Congenital Hypogonadotropic Hypogonadism: A Systematic Review and Meta-Analysis.

There is a lack of pooled data exploring the time and rates for human chorionic gonadotropin (hCG) monotherapy vs. combination therapies (hCG+human menopausal gonadotropin or recombinant human follicle-stimulating hormone) to restore spermatogenesis in azoospermic men with congenital hypogonadotropic hypogonadism (CHH). We aimed to investigate the time and rates to recover spermatogenesis among azoospermic CHH men receiving monotherapy vs. combination therapy. We conducted a systematic review and meta-analysis following the PRISMA guidelines. The search was performed on PubMed, EMBASE, Web of Science, and Scopus databases up to November 2023. Forrest plots were generated to visually present the pooled effect sizes for time to recover spermatogenesis, specifically employing the standardized mean difference (SMD). Publication bias was assessed utilizing funnel plots. PROSPERO ID: CRD42023473615. The search identified 720 studies meeting inclusion criteria. Our meta-analysis of 1,240 men with CHH revealed significant differences in the time to recover spermatogenesis between combination therapies and monotherapy. The weighted mean recovery time was significantly shorter for combination therapies (10 months) compared to monotherapy (33 months). The SMD under the common effect model was 8.8 for combination therapies and 24.98 for monotherapy, indicating a more rapid recovery with combination therapies, p<0.01. The rates of sperm recovery were 66.76% for combination therapies and 51.9% for monotherapy, p=0.03. Significant heterogeneity was observed in both groups (I²=86% for combination therapies and I²=68% for monotherapy), suggesting considerable variation in individual responses. The present meta-analysis reveals that in men with CHH, combination therapies expedite spermatogenesis recovery more than monotherapy. Additionally, combination therapies yield a higher rate of sperm appearing in the ejaculate as compared to hCG monotherapy. The significant heterogeneity observed in both groups underscores the variability in individual responses, warranting further investigation and caution in interpreting these results.

Sex differences in clinical characteristics and long-term outcome in patients with heart failure: data from the KorAHF registry.

Sex differences in the prognosis of heart failure (HF) have yielded inconsistent results, and data from Asian populations are even rare. This study aimed to investigate sex differences in clinical characteristics and long-term prognosis among Korean patients with HF. A total of 5,625 Korean patients hospitalized for acute HF were analyzed using a prospective multi-center registry database. Baseline clinical characteristics and long-term outcomes including HF readmission and death were compared between sexes. Women were older than men and had worse symptoms with higher N-terminal pro B-type natriuretic peptide levels. Women had a significantly higher proportion of HF with preserved ejection fraction (HFpEF). There were no significant differences in in-hospital mortality and rate of guideline-directed medical therapies in men and women. During median follow- up of 3.4 years, cardiovascular death (adjusted hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.07-1.78; p = 0.014), and composite outcomes of death and HF readmission (adjusted HR, 1.13; 95% CI, 1.01-1.27; p = 0.030) were significantly higher in men than women. When evaluating heart failure with reduced ejection fraction (HFrEF) and HFpEF separately, men were an independent risk factor of cardiovascular death in patients with HFrEF. Clinical outcome was not different between sexes in HFpEF. In the Korean multi-center registry, despite having better clinical characteristics, men exhibited a higher risk of all-cause mortality and readmission for HF. The main cause of these disparities was the higher cardiovascular mortality rate observed in men compared to women with HFrEF.

PRISE EN CAHRGE D’UN CANCER CANALAIRE INVASIF DU SEIN CHEZ UN HOMME DE 61 ANS A L’HOPITAL GYNECO-OBSTETRIQUE ET PEDIATRIQUE DE YAOUNDE : DIFFICULTES THERAPEUTIQUES

Introduction: Breast cancer, the leading malignant pathology in women, is still relatively rare in men. It accounts for less than 1% of malignant diseases in Men. Management strategies of breast cancer in males are copied from that of breast cancer in females. These therapies in men are in the experimentation stage despite the peculiarities observed. Hence, we are reporting the diagnosis and multidisciplinary management of a case of Invasive Ductal Carcinoma. Case presentation: we report the case of a 61-year-old male who consulted for a lump in the right breast discovered 3 years ago. Physical examination revealed an indurated nodular plaque (4x4x3cm) of the right breast located in the upper outer quadrant, not very tender not adherent to the superficial fascia. The overlying skin was macroscopically normal. Axillary palpation revealed homolateral axillary lymph nodes. The tumor was classified T2N1Mx. A breast ultrasound done revealed a lump of the right breast classified ACR4. Fine needle aspiration of the nodule as well as micro biopsy evoked an invasive grade 2 carcinoma. Neoadjuvant chemotherapy was done with cyclophosphamide. A right total Madden Mastectomy with homolateral lymphadenectomy was done. Progress postoperative was marked by local recurrence. Treatment with hormone therapy was initiated and radiotherapy delayed after secondary excision. We intended to show that tumor size, lymph node involvement and absence of hormone receptors are elements of poor prognosis just as a delay in radiotherapy is a risk for local recurrence. Conclusion: Male breast cancer is a rare pathology. Its management is copied exactly from that of the woman. Poor prognostic factors are: the size of the tumor, the presence of lymph nodes and the absence of hormone receptors. Keywords: breast cancer, male, prognosis, mastectomy, challenges

Hepcidin Reduction during Testosterone Therapy in Men with Type 2 Diabetes: A Randomized, Double-Blinded, Placebo-Controlled Study.

A randomized, placebo-controlled, double-blinded study at an academic tertiary-care medical center. Interventions were testosterone gel (TRT, n = 20) or placebo gel (n = 19) for 24 weeks. We included 39 men (50-70 years) with type 2 diabetes (T2D) on metformin monotherapy with bioavailable testosterone levels <7.3 nmol/L. Body composition was assessed with DXA- and MRI-scans; the main study outcomes were serum hepcidin-iron, FGF23, phosphate, klotho, and calprotectin. Hepcidin levels decreased during TRT (β = -9.5 ng/mL, p < 0.001), lean body mass (β = 1.9 kg, p = 0.001) increased, and total fat mass (β = -1.3 kg, p = 0.009) decreased compared to placebo. Delta hepcidin was not associated with changes in lean body mass or fat mass. Iron and the pathways of FGF23-phosphate-klotho and calprotectin were unchanged during TRT. During TRT, the reduction in hepcidin was not associated with circulating iron levels, lean body mass, or fat mass; these findings suggested a direct anti-inflammatory effect of TRT and no indirect effect mediated through these factors.

The effects of 12 weeks of high-intensity interval training and moderate-intensity continuous training on FGF21, irisin, and myostatin in men with type 2 diabetes mellitus

This study investigated the influence of a 12-week high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on irisin, fibroblast growth factor 21 (FGF21), and myostatin (MSTN) among men with type 2 diabetes mellitus (T2DM). Forty-five adult men with T2DM were randomly selected and assigned to receive and perform HIIT (4 × 4 min at 85–95% HRmax with three min of active rest at 50–60% HRmax in between) and MICT (walking/running continuously for 47 min at 60–70% HRmax) three sessions per week for 12 weeks, or to act as a non-exercise control (CON) group. The subjects’ blood samples were collected at baseline and 48 hours after the last intervention session. Our research revealed that both interventions resulted in similar decreases in FGF21 and MSTN when compared to the CON (p < .01). However, only the HIIT group showed a significant increase in irisin (p < .01) compared to the CON. Further, improvements in insulin resistance, body composition, and VO2 peak were noted in both intervention groups compared with those of the CON group (p < .01). It seems that while either aerobic exercise strategy could be seen as a therapy for men with T2DM, HIIT had a more advantageous effect on the irisin response.

Abstract 13067: Conduction System Pacing to Achieve Cardiac Resynchronization Therapy: Is There a Sex Difference in Response Rates?

Background: It is well established that in patients with dyssynchronous heart failure related to left bundle branch block (LBBB) and reduced left ventricular ejection fraction (LVEF), females show higher response rates than males when cardiac resynchronization (CRT) is achieved by conventional biventricular (BiV) pacing. Whether this sex difference is also true when CRT is achieved via conduction system pacing is unknown. Hypothesis: There is no difference between women and men in response rates when CRT is achieved by conduction system pacing (CSP), either by His bundle pacing (HBP) or by left bundle area pacing (LBAP). Methods: Patients who underwent CSP with a baseline LVEF ≤40% and a QRS duration ≥140 milliseconds (ms) were retrospectively selected from a CSP database maintained at our institution. 52 patients were included: 17 females and 35 males. Baseline clinical, electrocardiographic, echocardiographic, and follow up data were gathered and analyzed. Electrocardiograms and echocardiograms closest to the dates of implant and at last known follow up were used. Super-response was defined as absolute EF improvement ≥15%. Results: At baseline, there were no statistically significant differences in clinical, electrocardiographic, and echocardiographic characteristics between females and males except for higher prevalence of coronary disease in men, and higher percentage use of guideline directed medical therapy in men (Table 1). At median follow up of 113 days, there were no differences in electrocardiographic or echocardiographic response, number of super-responders, and mortality between females and males (Table 1). Conclusions: Unlike conventional CRT where females show superior response rates, CRT with CSP seems to provide comparable benefits in females and males. If confirmed in larger data sets, this may represent an important advantage of CSP over conventional CRT.

Validation of Biomechanical Computed Tomography for Fracture Risk Classification in Metastatic Hormone-sensitive Prostate Cancer

BackgroundGuidelines recommend dual-energy x-ray absorptiometry (DXA) screening to assess fracture risk and benefit from antiresorptive therapy in men with metastatic hormone-sensitive prostate cancer (mHSPC) on androgen deprivation therapy (ADT). However, <30% of eligible patients undergo DXA screening. Biomechanical computed tomography (BCT) is a radiomic technique that measures bone mineral density (BMD) and bone strength from computed tomography (CT) scans. ObjectiveTo evaluate the (1) correlations between BCT- and DXA-assessed BMD, and (2) associations between BCT-assessed metrics and subsequent fracture. Design, setting, and participantsA multicenter retrospective cohort study was conducted among patients with mHSPC between 2013 and 2020 who received CT abdomen/pelvis or positron emission tomography/CT within 48 wk before ADT initiation and during follow-up (48–96 wk after ADT initiation). Outcome measurements and statistical analysisWe used univariate logistic regression to assess the associations between BCT measurements and the primary outcomes of subsequent pathologic and nonpathologic fractures. Results and limitationsAmong 91 eligible patients, the median ([interquartile range) age was 67 yr (62–75), 44 (48.4%) were White, and 41 (45.1%) were Black. During the median follow-up of 82 wk, 17 men (18.6%) developed a pathologic and 15 (16.5%) a nonpathologic fracture. BCT- and DXA-assessed femoral-neck BMD T scores were strongly correlated (R2 = 0.93). On baseline CT, lower BCT-assessed BMD (odds ratio [OR] 1.80, 95% confidence interval or CI [1.10, 3.25], p = 0.03) was associated with an increased risk of a pathologic fracture. Lower femoral strength (OR 1.63, 95% CI [0.99, 2.71], p = 0.06) was marginally associated with an increased risk of a pathologic fracture. Neither BMD (OR 1.52, 95% CI [0.95, 2.63], p = 0.11) nor strength (OR 1.14, 95% CI [0.75, 1.80], p = 0.57) was associated with a nonpathologic fracture. BCT identified nine (9.9%) men eligible for antiresorptive therapy, of whom four (44%) were not treated. Limitations include low fracture numbers resulting in lower power to detect fracture associations. ConclusionsAmong men diagnosed with mHSPC, BCT assessments were strongly correlated with DXA, predicted subsequent pathologic fracture, and identified additional men indicated for antiresorptive therapy. Patient summaryWe assess whether biomechanical computer tomography (BCT) from routine computer tomography (CT) scans can identify fracture risk among patients recently diagnosed with metastatic prostate cancer. We find that BCT and dual-energy x-ray absorptiometry–derived bone mineral density are strongly correlated and that BCT accurately identifies the risk for future fracture. BCT may enable broader fracture risk assessment and facilitate timely interventions to reduce fracture risk in metastatic prostate cancer patients.

Serum Testosterone Concentration Influences the Response to Extracorporeal Shock Wave Treatment in Men With Peyronie's Disease

To assess the relationship between baseline total serum testosterone (T) and clinical outcomes in men affected by Peyronie's disease (PD) stable stage and treated by extra corporeal shockwave therapy (ESWT). In this study, 168 patients affected by PD in stable stage (≥12months) and treated with ESWT, were divided into 2 groups. Group 1 (G1) counted 71 patients with low T levels (≤ 300ng/dL); group 2 (G2) consisted of 97 patients with normal T that received ESWT with the same protocol of G1 for 6weeks. There were assessed at baseline and follow-up: Erectile dysfunction (ED), presence and severity of painful erections, penile plaque size, and penile curvature degree. The results were evaluated at baseline and 3, 6, 12, months after the treatment. Not statistically significant differences emerged between the 2 groups at baseline, except for higher presence of patients with ED in G1 (90%) vs G2 (52%). Three months after the treatment in G2 pain was resolved completely in 80.4% of the patients, compared with G1 (54.9%). G2 had a reduction of curvature degree after the 3-month treatment (P<.001). Mean plaque size decreased in both groups without statistically differences with baseline values. Mean±SD International Index of Erectile Function-5 score progressively improved significantly in the eugonadal men. This study demonstrated greater efficacy for the treatment of PD in men with normal T concentrations compared with men with low T concentrations. The results obtained from this study suggest that may be valuable in considering T therapy in men with PD prior to ESWT.

FRI444 Testosterone Therapy in Men with Classical vs Functional Hypogonadism: Results from a Controlled 9-year, Real-world Registry Study

Abstract Disclosure: M. Zitzmann: None. Background and Significance: Long-term data on Testosterone therapy (TTh) in hypogonadal men are limited and the clinical value, especially in men with functional hypogonadism (FH) is debated. A long-term, real-world registry study comprising groups of patients with hypogonadism of various etiologies provides a suitable and novel approach to this clinical issue. Methods: A registry spanning 9 years comprising 650 patients with hypogonadism included 188 patients with FH (mean age 42.3±11.3 years) and 462 men with classical hypogonadism (CH). Of these, 266 men had primary hypogonadism (PH, mean age 34.0±11.7 years) and 196 secondary hypogonadism (SH, mean age 31.9±12.0 years). All men uniformly received intramuscular T undecanoate (1000 mg). Effects of TTh on anthropometric parameters, as well as metabolic and safety parameters were compared. Results: The registry contained metabolic and safety parameters in individual duration of TTh spanning 1 to 9 years. Serum T concentrations increased from 6.6±2.4 nmol/L to 19.3±2.9 nmol/L in all patients (duration-of-treatment-dependent averages, mixed linear model for repeated measurements with the fixed variable “time x visit interaction”: p&amp;lt;0.001). In both categories of hypogonadism, TTh was associated with significant weight loss and decrease in waist circumference (WC, both p&amp;lt;0.001). Cox regression and Kaplan-Meier models revealed differences of inter-individual check-points: men with FH were more likely to lose &amp;gt;10% weight and &amp;gt;5% of WC than men with CH (hazard ratio 1.3 [1.1-1.4], p=0.008 and hazard ratio 1.4 [1.3-1.5], p=0.001). There was no difference between groups for the overall marked increase in hematocrit. Changes in PSA levels were more likely to occur in FH (hazard ratio 1.3 [1.1-1.6], p=0.003). During TTh, patients with FH exhibited significantly more pronounced changes of favourable nature in metabolic parameters than patients with CH (total cholesterol, triglycerides, LDL- and HDL-cholesterol and fasting glucose). The same applied to scores of AMS and IIEF-EF questionnaires. Effects on most parameters, especially hematocrit, were significantly modulated by age and baseline values for weight, WC und T. Conclusions: Findings regarding effects and safety of TTh in different groups of hypogonadal men are provided. Effects on factors associated with cardiovascular health are modulated by diagnosis and age. Patients with FH seem to benefit to a larger extent from TTh, most likely attributable to their more pronounced risk factor profile at baseline. Presentation Date: Friday, June 16, 2023

SAT413 Feminising Gender Affirming Hormone Therapy Prolongs QTc Interval

Abstract Disclosure: L. Angus: Speaker; Self; Kirin Brewery. T. Lin: None. S. Leemaqz: None. M. Grossmann: None. J.D. Zajac: None. A.S. Cheung: None. Background: In trans people using feminising hormone therapy there is an increased risk of cardiovascular events including conduction disorders. It is known that the QTc interval is longer in cisgender women of reproductive age than cisgender men, attributed to factors including serum sex steroid concentrations. Androgen deprivation therapy in men with prostate cancer is associated with prolongation of the QTc interval, but the effects of feminising hormone therapy in trans women are unclear. Methods: We measured the automated QTc interval from a 12-lead electrocardiogram at baseline and 6 months in trans women newly commencing feminising hormone therapy. Sex steroid concentrations were measured by LCMS. Participants were part of a randomised controlled double-blind trial of spironolactone 100mg daily versus cyproterone acetate 12.5mg daily in transgender women commencing estradiol for feminisation (ANZCTR 12620000339954) and this was a prespecified secondary outcome. Statistical analysis was performed using a linear mixed effects model looking at the effects of treatment over time. Results: Sixty-three participants were randomised and 55 participants completed the trial and were included in analysis (spironolactone group n=27, cyproterone acetate group n=28). Baseline group characteristics were comparable. Overall, the QTc interval increased by 18ms (95% CI 14 - 23 ms; p&amp;lt;0.001) at 6 months compared to baseline, but there was no between group difference (p=0.23). One participant had a QTc interval above 450ms. The mean serum total testosterone concentrations were similar between groups at baseline (spironolactone group 16.9 (13.5 - 20.3) nmol/L vs cyproterone acetate group 18.0 (15.0 - 21.0) nmol/L, p=0.60) but higher in the spironolactone group 4.3 (2.0 - 6.5) nmol/L than the cyproterone acetate group 1.5 (0.0 - 2.9) nmol/L, p&amp;lt;0.05 at 6 months. The mean serum estradiol and serum potassium concentrations were similar between groups at baseline and 6 months. Conclusions: Feminising hormone therapy with estradiol and either spironolactone or cyproterone acetate in trans women is associated with prolongation of the QTc interval over a six-month period. Further research is required to investigate the incidence of cardiac arrhythmia in this population. Presentation: Saturday, June 17, 2023

P-013 Evaluation of the efficacy of a short course of multidose menotropins in the treatment of male infertility in real clinical practice

Abstract Study question Is it possible to establish prognostic criteria for response to short course of multidose menotropin therapy in men with sperm pathology. Summary answer We found the increase of the effectiveness of menotropins with an increase in the duration of their use and an increase in dosage. What is known already Currently, menotropins are widely used to treat male infertility, both to stimulate spermatogenesis and to compensate for hormonal imbalance. But the actual practice of using menotropins may differ from the recommendations given by the manufacturer. Therefore, observational programs are particularly important, which allow assessing the effectiveness of a drug in routine practice. In real-world practice, hormonal treatment of the infertility is often carried out during the preparation of a couple for IVF and lasts no more than 4-6 weeks. At the same time, there is almost no scientific data in the literature of the effectiveness of such short treatment regimens. Study design, size, duration The study was designed as a multicentre, prospective, observational cohort study. The study included 1117 men with infertility enrolled between January 2020 and April 2021. Participants/materials, setting, methods The study included men with the absence of pregnancy during 12 months of regular unprotected sexual activity. The average duration of infertility was 20.6 months. As a treatment, men received multidose menotropin at a dosage of 75 IU, 112.5 IU or 150 IU every other day with hCG 2000 IU 2-3 times a week. Sperm parameters and hormones (total testosterone, SHBG, LH, FSH, Inhibin B, estradiol) were evaluated before treatment and 4 weeks after. Main results and the role of chance The age of the patients was 18 to 65 years (33.6 ± 7.0 years). The sperm concentration after 1 month of treatment increased by 23.8% from 17.6±18.1 to 23.1 million/ml, the total sperm count increased by 32.1% from 40.2±41.7 to 53.1± 49.1 million, progressive motility increased on average from 26.5±16.2 to 32.0±16.5%, the proportion of morphologically normal spermatozoa increased from 2.3±2.5 to 3.0±2.7 %. The level of total testosterone increased by 33.3% from 11.1±4.6 to 14.8±6.3 nmol/l. The levels of Inhibin B and estradiol did not change significantly. In a comparative analysis of the effect of dosage on the parameters of the ejaculate, the dose of 112.5 IU showed the greatest effect. Limitations, reasons for caution The main limitation of this study is the large heterogeneity of enrolled patients. There will be a very large variability in the age of men, as well as the severity of deviations from the norm in the analysis of ejaculate. Wider implications of the findings Thus, multidose menotropin, already when used for 4 weeks, can significantly improve the quality of the ejaculate (concentration, total count, progressive motility, morphology). In case of insufficient effectiveness of a short course (1 month), it is advisable to continue treatment for at least 3 months or increase the dosage. Trial registration number not applicable

Effect of the personality traits of healthy Japanese workers on depressive symptoms and social adaptation, and on the achievement rate of exercise therapy to prevent major depression.

This study determined the effects of personality traits on depressive symptoms and social adaptation in healthy workers, and the effects of depressive symptoms or social adaptation before and after exercise therapy, and personality traits before exercise therapy on the achievement rates of exercise therapy aimed at preventing major depression. Two hundred fifty healthy Japanese workers were given an eight-week walking program as exercise therapy. After excluding 35 participants who had dropped or provided incomplete information, 215 were included in the analysis. The Japanese version of the NEO five-factor inventory was used to assess participants' personality traits before the exercise therapy. Depressive symptoms were evaluated using the Japanese version of the Zung self-rating depression scale (SDS-J) and social adaptation was evaluated using the Japanese version of the social adaptation self-evaluation scale (SASS-J) before and after the exercise therapy. The SDS-J scores correlated with neuroticism and negatively correlated with extraversion, agreeableness, and conscientiousness before the exercise therapy. The SDS-J was also negatively correlated with openness in women, but not in men, while the SASS-J was associated with extraversion, openness, agreeableness, and conscientiousness, and negatively correlated with neuroticism. There was no significant change in levels of depression before and after exercise therapy; however, social adaptation increased significantly in men. No association was found between SDS-J and SASS-J scores before the exercise therapy and the achievement rate. The achievement rates of exercise therapy were negatively correlated with SDS-J or SASS-J after exercise therapy in women. The SDS-J after exercise therapy was correlated with neuroticism in men and negatively correlated with extraversion in women. The SASS-J after exercise therapy was negatively correlated with neuroticism and correlated with extraversion and openness in men. In contrast, the SASS-J after exercise therapy correlated with openness and agreeableness in women. Conscientiousness was correlated with the achievement rate of exercise therapy in men, but not with the various personality traits in women. Depressive symptoms and social adaptation were differently associated with personality traits and achievement rates before and after exercise therapy. Conscientiousness before exercise therapy predicted a higher achievement rate for exercise therapy in men.

The Impact of Medicare Low-income Subsidy on Access to Treatment, Treatment Choice, and Oncologic Outcomes in Patients With Metastatic Prostate Cancer.

Patients eligible for Medicare Part D low-income subsidy have lower cost-sharing for both IV and oral cancer therapies. We evaluated associations between low-income subsidy and treatment choice, treatment initiation, and overall survival in patients with metastatic prostate cancer. We identified men aged 66 years and older diagnosed with stage IV prostate cancer between 2010 and 2017 included in the Surveillance, Epidemiology, and End Results-Medicare linked data set. Using linear probability models, we evaluated the impact of low-income subsidy on type of first supplementary treatment (oral vs IV) among patients who received nonandrogen deprivation therapy supplementary systemic therapy, and initiation of any nonandrogen deprivation therapy supplementary systemic therapy. Overall survival was estimated with Kaplan-Meier curves. Of the 5,929 patients included, 1,766 (30%) had low-income subsidy. On multivariable analysis, those with low-income subsidy were more likely to receive oral as opposed to IV treatments compared to patients without low-income subsidy (probability difference: 17%, 95% CI 12, 22). However, patients with low-income subsidy were less likely to initiate any nonandrogen deprivation therapy supplementary systemic therapy (oral or IV) compared to those without low-income subsidy (probability difference: 7.9%, 95% CI 4.8-11). Additionally, patients with low-income subsidy experienced worse overall survival than those without low-income subsidy (P < .001). While low-income subsidy was associated with increased use of more expensive oral therapies in men with metastatic prostate cancer, barriers to accessing these treatments still exist. These findings stress the importance of continued efforts to improve health care access to low-income individuals.

Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial

Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. Pfizer.

Phase III study of local or systemic therapy intensification directed by PET in prostate cancer patients with post-prostatectomy biochemical recurrence (INDICATE): ECOG-ACRIN EA8191.

TPS5118 Background: Salvage radiation therapy (sRT) to the prostate bed and pelvic nodes with short-term androgen deprivation therapy (STAD) is considered a standard of care (SOC) salvage therapy (ST) paradigm for prostate cancer (PC) patients (pts) with post-prostatectomy (RP) biochemical recurrence (BCR). PET imaging with recently FDA-approved agents in this setting (18F-Fluciclovine, 18F-DCFPyL and 68Ga-PSMA-11), have shown improved accuracy for detection of metastases not identified with conventional imaging (CIM). Given the greater sensitivity and specificity of PET, its findings are being increasingly but variably applied to justify modification or omission of SOC therapies without high-level evidence of clinical benefit. PET may help identify candidates for different treatment intensification approaches. In metastatic prostate cancer, metastasis-directed RT (MDT) has been used to avoid or delay systemic therapy in men with oligometastatic disease. Apalutamide (Apa) is an androgen receptor signaling inhibitor that has been shown to improve outcomes when added to ADT in mCSPC. This study will evaluate whether patients with PET-detected lesions outside the pelvis will benefit from addition of MDT to treatment intensification with STAD/Apa, and whether patients with no PET-detected lesions outside the pelvis will benefit from addition of Apa to standard sRT/STAD. Methods: PC pts with post-RP BCR (PSA &gt; 0.5ng/mL; &gt; 0.2ng/mL if first detectable within 12 mos of RP) and no extrapelvic metastases on CIM who are candidates for SOC ST (sRT to prostate bed and pelvic nodes with STAD) are eligible. Pts will undergo SOC baseline PET using a FDA-approved tracer. Based on institutional clinical interpretation of the SOC PET, pts will be placed in Cohort 1 (PET-negative) or 2 (PET-positive for extra-pelvic metastases). Cohort 1 will be randomized to SOC ST +/- Apa for 6 months and Cohort 2 will be randomized to SOC ST and Apa +/- MDT to PET-positive lesions. The primary endpoint is PFS, defined as time from randomization to radiographic progression on CIM, symptomatic disease or death, whichever occurs first. Primary objectives are to evaluate whether addition of Apa to SOC ST and addition of MDT to SOC ST and Apa could prolong PFS in Cohorts 1 and 2, respectively. For Cohort 1, 480 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 90% (Apa arm) vs. 80% (SOC arm) using one-sided stratified logrank test with type I error of 0.025. For Cohort 2, 324 pts will be randomized with 85% power to distinguish a 5-year PFS rate of 76.5% in the experimental arm from 61.5% in the control arm. Secondary endpoints include overall and event-free survival, toxicity, PET progression and quality of life. Clinical trial registry number: NCT04423211. Clinical trial information: NCT04423211 .

Sex-specific analysis of the rapid up-titration of guideline-directed medical therapies after a hospitalisation for acute heart failure: insights from the STRONG-HF trial.

The aim of this study was to evaluate efficacy and safety of rapid up-titration of guideline directed medical therapies in men and women hospitalized for acute heart failure (AHF). In STRONG-HF AHF patients were randomised just prior to discharge to either usual care (UC) or a high-intensity care (HIC) strategy of guideline-directed medical therapies (GDMT) up-titration. In these analyses, we compare the implementation, efficacy, and safety of the HIC strategy between men and women. In the randomised AHF population, 416/1078 (39%) were women. By day 90, a higher proportion of both sexes in the HIC group had been up-titrated to full doses of GDMT compared to UC. Overall, there were no differences in the primary endpoint between the sexes. The primary endpoint, 180-day HF readmission or death, occurred in 15.8% HIC women vs 23.5% women in the UC group (adjusted HR 0.67 [95% CI 0.40-1.13]) and in 14.9% HIC men vs 23.5% UC men (adjusted HR 0.57 [95% CI 0.38-0.88]), adjusted interaction p = 0.65. There was no significant treatment-by-sex interaction in quality-of-life improvement or in adverse events, including serious or fatal adverse events. The results of the current analyses suggest that a rapid up-titration of GDMT immediately after an AHF hospitalisation can and should be implemented similarly in men and women, as it results in reduction of 180-day all-cause death or HF readmission, quality-of-life improvement in both men and women with a similar safety profile.

Differential tumor gene expression profiling of obese and non-obese patients (pts) with prostatic adenocarcinoma (PC).

5075 Background: Increased baseline body mass index (BMI) has been linked to poorer prostate cancer outcomes, including recurrence, reduced quality of life, and mortality (PMID: 21325564, 17211863). Herein, we sought to interrogate and validate the corresponding differences in tumor gene expression profiles of obese (Ob) vs. non-obese (N-Ob) pts with PC. Methods: In this IRB-approved retrospective study, eligibility criteria included histologically confirmed PC and available RNA sequencing results from treatment naïve primary prostate tissue from a CLIA-certified lab (either Tempus or Caris Life Sciences). Tempus cohort was used for interrogation and Caris for validation. Pts in each cohort were categorized into two groups: obese (BMI≥30) and non-obese (BMI&lt;30). BMI at the time of diagnosis of PC was used for analysis. The DEseq2 pipeline was used to analyze differentially expressed genes between the groups. The data included the Log2 fold change, Wald-Test p-values, and Benjamini-Hochberg adjusted p-values for each differentially expressed gene. These results were subjected to Gene Set Enrichment software analysis (GSEA) to identify pathways enriched in each cohort. All bioinformatic analysis was undertaken using R v4.2. Results: Tempus cohort: n=60 (Ob =22, N-Ob=38); Caris cohort: n=50 (Ob=17, N-Ob=33). Both Tempus and Caris showed that Ob pts had an increased expression of the heme metabolism, androgen response, protein secretion, fatty acid, and bile metabolism pathways. N-Ob pts had a significantly higher expression of genes involved in the inflammation pathways (interferon-alpha &amp; TNF alpha pathways). Normalized enrichment scores are reported in the table. Differential gene set expression analysis in Ob vs. N-Ob pts with PC. Conclusions: Our study showed an upregulation of distinct genomic pathways in Ob pts with prostate cancer. For example, Ob pts with PC have tumors that depend more on androgen signaling, and N-Ob pts' tumors express increased inflammatory pathway genes that promote PC growth, invasiveness, and metastasis. After external validation, these hypothesis-generating data may provide the rationale for personalized therapy in men with PC. [Table: see text]

(077) Testosterone Therapy in Men on Active Surveillance for Prostate Cancer

Abstract Introduction The role of testosterone therapy (TTH) in men with prostate cancer (PC) is debated, especially in men on active surveillance (AS). Objective This study aimed to review our data on TTH in this population. Methods The study population consisted of (i) men with PC on active surveillance (ii) with two total T (TT) levels &amp;lt;300 ng/dL (iii) associated with symptoms (iii) performed using LCMS (v) conducted in an early morning fashion who (vi) pursued T therapy (TTH). TTH included exogenous (transdermal, intramuscular) and clomiphene citrate (CC) in the setting of low/low-normal LH levels. T lab work including PSA levels, were checked within 4 weeks of TTH initiation, every three months in the first year and every six months after that. Target TT level was the middle tertile of the normal reference range at our institution. We report on T and PSA levels in this group. Results 82 patients are included. Mean age = 64 ± 9 years. Median pre-TTH PSA levels were 4.6 [3.4, 6.7] ng/mL. Mean baseline TT levels were 305 ± 145 ng/dL. 19% of these men had a TT level &amp;lt;200 ng/dL. Median Gleason score (GS) was 6 with 90% 3+3, 9% 3+4 and 1% 4+3. Median duration on AS before TTH was 14 [1, 43] months. 45% received transdermal T, 19% intramuscular T and 36% CC. Post-TTH TT = 553 ± 268 ng/dL, PSA = 4.9 [3.2, 9.2] Median duration of TTH at last follow-up was 14 [1, 39] months. Median PSA change per patient was 0.3 [-0.9, 2.6] ng/mL, representing a median of 14 (-24, 70) % change in PSA per patient (p= 0.045). 42% had a decrease in PSA, 58% an increase. In 88% of men who experienced a rise in PSA, the PSA rose ≥10%. 50% of men on TTH who had a PSA level below 4 ng/dL rose above 4. 28% of men experienced a PSA level increase ≥1 ng/mL per year. In 18% of these men, TTH was stopped and definitive PC treatment was instituted. In men with ≤1 ng/mL per year increase in PSA, another 18% opted for definitive PC treatment. The most common reason for this was PSA anxiety. Conclusions In men with PC on AS treated with TTH, minimal changes in PSA were seen, with equal numbers of men experiencing a rise and a drop in PSA. About fifth of men ceased AS and proceeded to definitive therapy for their PC. Disclosure No

(070) Testosterone Therapy in Men with Klinefelter Syndrome: Analysis of a Global Federated Research Network

Abstract Introduction Klinefelter syndrome (KS) is a genetic condition in which a male is born with an extra X-chromosome and is one of the on-label indications for testosterone replacement therapy (TRT). The prevalence of testosterone deficiency in men with KS is difficult to predict and not well described in the literature. Furthermore, there is no previous literature detailing the rates of TRT prescription in men diagnosed with KS. Objective We aimed to determine the rates of hypogonadism and prescription of TRT in men with KS using a large, federated research database. We hypothesized that men with KS are undertreated for testosterone deficiency with TRT due to a combination of factors including a poor understanding of hypogonadism in this population and neurocognitive issues leading to delay in seeking treatment for hypogonadism. Methods We queried TriNetX, a large, multicenter electronic health record database, to identify all men with a diagnosis of Klinefelter syndrome (ICD-10-CM Q98.4) excluding men with prescription of TRT prior to diagnosis of KS or a diagnosis of KS more than 20 years ago. Descriptive analysis on associated comorbidities and demographic characteristics was performed. We then filtered the initial cohort to find men who received a laboratory measurement of testosterone level on the day of diagnosis with KS or later. Prevalence of testosterone deficiency was determined as defined by testosterone level &amp;lt; 300 ng/dl. The primary outcome of the study was prescription of any of the following forms of TRT on the day of diagnosis or later using associated medication codes: testosterone, testosterone 17-phenylpropionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate. Rates of TRT prescription were determined for both the initial cohort and the hypogonadal subgroup. Results There were 5,437 total men with diagnosis of KS. A total of 1,581 men with KS received laboratory measurement of testosterone level, 1,113 (70.4%) of whom were hypogonadal. Mean testosterone level in this group was 354 ng/dL [50 – 658]. Of the 1,113 men found to be hypogonadal, only 657 (59.0%) men were given prescription for TRT. Conclusions This is the first study to evaluate TRT prescribing habits in men with KS. In this large, retrospective study, TRT was under-prescribed in men with KS. Further studies are needed to corroborate these findings and to evaluate the barriers to receiving care in this population. Disclosure No

(496) Effects of Long-term Testosterone Therapy in Men with Functional Hypogonadism and Obesity on the Lipid Pattern – Results from a Registry Study

Abstract Introduction The lipid pattern plays a role in the assessment of cardiometabolic risks such as atherogenicity (non-HDL), arteriosclerotic cardiovascular disease (remnant cholesterol), or insulin resistance (TG:HDL ratio). A recent meta-analysis suggested that, in patients with metabolic disorders, only a reduction of triglycerides achieved statistical significance across controlled and uncontrolled studies (Corona G et al. Exp Rev Clin Pharmacol 2021;14:1091-1103). The lipid pattern plays a role in the assessment of cardiometabolic risks such as atherogenicity (non-HDL), arteriosclerotic cardiovascular disease (remnant cholesterol), or insulin resistance (TG:HDL ratio). A recent meta-analysis suggested that, in patients with metabolic disorders, only a reduction of triglycerides achieved statistical significance across controlled and uncontrolled studies (Corona G et al. Exp Rev Clin Pharmacol 2021;14:1091-1103). Another recent meta-analysis suggested significant reductions of total cholesterol, LDL, HDL and triglycerides (Hudson J et al. Lancet Healthy Longev 2022;3:e381–93). Objective to investigate effects of long-term TTh up to 13 years on the lipid pattern in men with functional hypogonadism and obesity compared to an untreated control group. Methods In an ongoing registry study in men with hypogonadism (total testosterone ≤350 ng/mL and at least moderate symptoms on the Aging Males’ Symptoms scale, AMS) in a single urology office, 491 men had functional hypogonadism and obesity (BMI ≥30 kg/m2). 292 men received testosterone undecanoate (TU) injections 1000 mg/12 weeks following an initial 6-week interval (T-group), 199 opted against TTh and served as controls (CTRL). Total cholesterol, LDL, HDL, and triglycerides were assessed at each visit. Absolute measures with standard deviations (SDs) as well as changes over time, adjusted for age, weight, waist circumference, fasting glucose, blood pressure, lipids, and quality of life to account for baseline differences between groups, are reported for a duration of 13 years. Results Mean (median) follow-up: T-group 10.1±3.1 (11), CTRL 9.4±3.3 (10) years, total observation time: T-group 2944, CTRL 1861 patient-years. Baseline age: 59.5±6.0 (T-group) and 63.0±5.0 years (CTRL) (p&amp;lt;0.0001). Total cholesterol (TC) (mmol/L for all lipids) decreased by 2.9±0.1 (least squares means ± SEs) from 8.2±1.0 to 5.1±0.3 (means ± SDs) in T-group and increased by 1.38±0.1 from 7.3±1.0 to 8.6±1.2 in CTRL (p&amp;lt;0.0001 for all). HDL increased by 0.5±0.0 from 1.0±0.4 to 1.6±0.3 in T-group and decreased by 0.4±0.0 from 1.1±0.5 to 0.8±0.4 in CTRL (p&amp;lt;0.0001 for all). The TC:HDL ratio decreased by 5.4±0.2 from 9.2±3.8 to 3.4±0.6 in T-group and increased by 6.5±0.3 from 8.0±3.8 to 12.6±5.8 in CTRL (p&amp;lt;0.0001 for all). LDL decreased by 1.9±0.0 from 4.5±0.9 to 2.5±0.3 in T-group and increased by 1.2±0.1 from 4.2±1.3 to 5.4±1.3 in CTRL (p&amp;lt;0.0001 for all). Triglycerides (TG) decreased by 1.1±0.0 from 3.4±0.5 to 2.2±0.1 in T-group and increased by 0.7±0.0 from 3.2±0.5 to 3.9±0.5 in CTRL (p&amp;lt;0.0001 for all). Non-HDL decreased by 3.4±0.1 from 7.2±1.0 to 3.5±0.2 in T-group and increased by 1.6±0.1 from 6.2±1.1 to 7.8±1.3 in CTRL (p&amp;lt;0.0001 for both). Remnant cholesterol decreased by 1.5±0.1 from 2.7±0.9 to 1.0±0.3 in T-group and increased by 0.5±0.1 from 2.1±1.0 to 2.4±0.7 in CTRL (p&amp;lt;0.0001 for both). The TG:HDL ratio decreased by 5.0±0.2 from 8.7±3.9 to 3.2±0.6 in T-group and increased by 6.8±0.3 from 8.1±3.9 to 13.6±6.7 in CTRL (p&amp;lt;0.0001 for both). Conclusions Long-term TTh in men with functional hypogonadism and obesity improved all components of the lipid pattern. In the untreated control group, the lipid pattern deteriorated. Disclosure Yes, this is sponsored by industry/sponsor: Bayer AG, Berlin, Germany. Clarification Industry funding only - investigator initiated and executed study. Any of the authors act as a consultant, employee or shareholder of an industry for: Bayer AG.