Androgen Deprivation Therapy In Men Research Articles

Development of depression in patients using androgen deprivation therapy: A systemic review and meta-analysis.

Androgen deprivation therapy (ADT) is an effective treatment for advanced prostate cancer (PCa). Multiple studies have highlighted serious consequences this therapy poses to mental health, particularly depression. We aimed to review the incidence and association between ADT in men with PCa and the risk of depression. We systematically searched multiple databases, including MEDLINE, Scopus till August 2023 for studies that compared ADT versus control for treating PCa reporting depression as outcome. Meta-analysis was performed using random-effects models and results presented as odds ratios (ORs) with 95% confidence interval (CI). Quality assessment of the included studies was conducted using Joanna Briggs Institute critical appraisal checklists. A total of 38 studies (17 retrospective studies, 16 prospective studies, two cross-sectional studies and two randomized trials) with 360,650 subjects met the inclusion criteria and were included in this meta-analysis. The estimated pooled incidence of depression among ADT patients is 209.5 (95% CI = 122.3; 312.2) per 1000 patients. There is statistically significant relationship between ADT treatment and depression (OR = 1.46, 95% CI = 1.28, 1.67; p = 0, I2 = 86.4%). The results remained consistent across various subgroups. No risk of publication bias was detected by funnel plot and Eggers's test (p > 0.05). There is a higher risk of depression for men receiving ADT. Further studies evaluating optimal treatments for depression in men on ADT are warranted.

Clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular toxicity from androgen deprivation therapy in men with prostate cancer.

312 Background: Androgen deprivation therapy (ADT) with agonists of the gonadotropin releasing hormone (GnRH) receptor (e.g. leuprolide) is associated with coronary artery disease and major adverse cardiovascular (CV) events. CHIP, an age-related expanded somatic blood cell clone without other hematologic abnormalities, is associated with inflammation and accelerated atherosclerosis. Whether CHIP is associated with adverse CV outcomes in patients receiving ADT is unknown. Methods: Twenty-five men with localized prostate cancer pursuing radiotherapy plus ≥ 6 months of leuprolide were enrolled on a prospective biorepository. Using pre-treatment blood samples, whole exome sequencing libraries were generated; identified variants were filtered to retain <1% MAF variants found amongst the three most common CHIP genes ( DNMT3A, TET2, ASXL1). Pre-treatment and 6-month blood samples from each patient subsequently were analyzed using a commercially available, validated 4-protein risk score that is predictive of 4-year major adverse CV events (Prevencio Inc HART CVE, Seattle WA). Multivariable logistic regression measured the association of CHIP with increased CV risk after initiation of leuprolide, defined as a clinically significant rise in 4-protein risk score at six months compared with baseline. Results: Median age was 70 years (IQR 65-76), 10 men (40%) were Black, and 4 men (16%) had a history of myocardial infarction. CHIP gene variants were found in 7 men (28%). Amongst the men with CHIP variants, 6 (85.7%) were Black. Amongst the entire cohort, 11/25 (44%) men had a clinically significant rise in CV risk score after six months of ADT. These men, compared with those who did not experience a rise in CV risk, were more often Black (72.7% versus 14.3%), on anti-hypertensive medication (72.7% versus 14.3%), and had higher baseline LDL cholesterol level (median 98 versus 81 mg/dL). On univariate analysis, harboring ≥1 CHIP variant was associated with a significantly increased odds of having an elevated CV risk score after 6 months of ADT. On multivariable analysis, after adjusting for race, anti-hypertensive medication use, and baseline LDL cholesterol, harboring ≥1 CHIP variant was associated with increased odds of having an elevated CV risk score after 6 months of ADT (adjusted OR 1.44, 95% CI 0.88-1.83), which did not meet statistical significance but limited by small sample size. Conclusions: Six months of GnRH-agonist leuprolide resulted in a rise in CV risk score in 44% of this cohort. CHIP variants, identified in 28% of this cohort, was associated with increased odds of experiencing a rise in CV risk score. Notably, Black men were more likely to harbor CHIP and experience increased CV risk after 6 months of leuprolide, respectively. Larger studies are underway to determine if CHIP variants may serve as a biomarker of ADT-induced CV risk, especially in older Black men.

Prostate-Specific Antigen Response to Androgen Deprivation Therapy in the Neoadjuvant Setting for High-Risk Prostate Adenocarcinoma (PIRANHA): Pooled Analysis of Two Randomized Clinical Trials

A suboptimal prostate-specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) among men who go on to receive definitive radiation therapy for prostate cancer might suggest the existence of castration-resistant disease or altered androgen receptor signaling. This in turn may portend worse long-term clinical outcomes, especially in men with high-risk disease. We set out to evaluate the prognostic impact of poor PSA response to neoadjuvant ADT in men with high-risk prostate cancer. This was a post hoc analysis of the multicenter TROG 03.04 RADAR and PCS IV randomized clinical trials. Inclusion criteria for this analysis were patients with high-risk prostate cancer (defined as Gleason score ≥8, initial PSA ≥20 ng/mL, or cT3a disease or higher) who received definitive radiation therapy, at least 18 months of ADT, and had a preradiation therapy PSA level drawn after at least 3 months of neoadjuvant ADT. Poor PSA response was defined as PSA >0.5 ng/mL. Cox regression and Fine-Gray models were used to test whether poor PSA response was associated with metastasis-free survival, biochemical recurrence, prostate-cancer specific mortality, and overall survival. Nine hundred thirty men met inclusion criteria for this analysis. Median follow-up was 130 months (interquartile range [IQR], 89-154 months). After a median of 3 months (IQR, 3-4.2 months) of neoadjuvant ADT, the median PSA was 0.60 ng/mL (IQR, 0.29-1.59). Overall, 535 men (57%) had a PSA >0.5 ng/mL. Poor PSA response was associated with significantly worse metastasis-free survival (hazard ratio [HR], 3.93; P=.02), worse biochemical recurrence (subdistribution HR, 2.39; P=.003), worse prostate-cancer specific mortality (subdistribution HR, 1.50; P=.005), and worse overall survival (HR, 4.51; P=.05). Patients with PSA >0.5 mg/mL after at least 3 months of neoadjuvant ADT had worse long-term clinical outcomes and should be considered for treatment intensification.

Randomized Trial of Concomitant Hypofractionated Intensity Modulated Radiation Therapy Boost Versus Conventionally Fractionated Intensity Modulated Radiation Therapy Boost for Localized High-Risk Prostate Cancer (pHART2-RCT)

The aim of this work is to report on the results of a phase 2 randomized trial of moderately hypofractionated (MH) versus conventionally fractionated (CF) radiation therapy to the prostate with elective nodal irradiation. This was a single-center, prospective, phase 2 randomized study. Patients with high-risk disease (cT3, prostate-specific antigen level >20 ng/mL, or Gleason score 8-10) were eligible. Patients were randomized to either MH using a simultaneous integrated boost (68 Gy in 25 fractions to prostate; 48 Gy to pelvis) or CF (46 Gy in 23 fractions with a sequential boost to the prostate of 32 Gy in 16 fractions), with long-term androgen deprivation therapy. The primary endpoint was grade ≥2 acute gastrointestinal (GI) and genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 3.0). Secondary endpoints included late GI and GU toxicity, quality of life, and oncologic outcomes. One-hundred eighty patients were enrolled; 90 were randomized to and received MH and 90 to CF. The median follow-up was 67.4 months. Seventy-five patients (41.7%) experienced a grade ≥2 acute GI and/or GU toxicity, including 34 (37.8%) in the MH and 41 (45.6%) in the CF arms, respectively (P = .29). Late grade ≥2 GI (P = .07) and GU (P = .25) toxicity was not significantly different between arms; however, late grade ≥3 GI toxicity was worse in the MH group (P = .01). There were no statistically significant quality-of-life differences between the 2 treatments. There were no statistically significant differences observed in cumulative incidence of biochemical failure (P = .71) or distant metastasis (P = .31) and overall survival (P = .46). MH to the prostate and pelvis with androgen deprivation therapy for men with high-risk localized prostate cancer was not significantly different than CF with regard to acute toxicity, quality of life, and oncologic efficacy. However, late grade ≥3 GI toxicity was more common in the MH arm.

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<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<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

Chemotherapy for the initial treatment of metastatic prostate adenocarcinoma and neuroendocrine carcinoma at diagnosis: real world application and impact in the SEER database (2004 -2018).

Randomized controlled phase III trials have reported significant improvements in disease response and survival with the addition of chemotherapy to androgen deprivation therapy for men presenting with metastatic prostate cancer. We examined the implementation of such knowledge and its impact within the Surveillance, Epidemiology, and End Results (SEER) database. The administration of chemotherapy for men with an initial presentation of metastatic prostate cancer from 2004 to 2018 in the SEER database and its association with survival outcomes was examined. Kaplan-Meier estimates were applied to compare survival curves. Cox proportion hazard survival models were used to analyze the association of chemotherapy and other variables with both cancer- specific and overall survival. A total of 727,804 patients were identified with 99.9% presenting with adenocarcinoma and 0.1% with neuroendocrine histopathology. Chemotherapy as initial treatment for men with de novo distant metastatic adenocarcinoma increased from 5.8% during 2004-2013 to 21.4% during 2014-2018. Chemotherapy was associated with a poorer prognosis during 2004-2013 but was associated with improved cancer-specific (hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.78-0.93, p=0.0004) and overall survival (HR= 0.78, 95% CI: 0.71-0.85, p < 0.0001) during 2014-2018. The improved prognosis during 2014-2018 was observed in patients with visceral or bone metastasis and most impactful for patients aged 71-80 years. These findings were confirmed by subsequent propensity score matching analyses. Furthermore, chemotherapy was consistently provided to 54% of patients with neuroendocrine carcinoma at diagnosis from 2004 to 2018. Treatment was associated with improved cancer-specific survival (HR= 0.62, 95% CI: 0.45-0.87, p=0.0055) and overall survival (HR= 0.69, 95% CI: 0.51-0. 94, p=0.0176) during 2014-2018 but not significant in earlier years. Chemotherapy at initial diagnosis was increasingly employed in men with metastatic adenocarcinoma after 2014 and consistent with the evolution of National Comprehensive Cancer Network (NCCN) guidelines. Benefits for chemotherapy are suggested after 2014 in the treatment of men with metastatic adenocarcinoma. The use of chemotherapy for neuroendocrine carcinoma at diagnosis has remained stable, and outcomes have improved in more recent years. Further development and optimization of chemotherapy continues to evolve for men with de novo diagnosis of metastatic prostate cancer.

A phase 2 randomized open-label study of oral darolutamide monotherapy vs. androgen deprivation therapy in men with hormone-naive prostate cancer (EORTC-GUCG 1532).

160 Background: Darolutamide is androgen-receptor (AR) inhibitor with low blood–brain barrier penetration and limited potential for clinically relevant drug–drug interactions. Darolutamide has been shown to increase overall survival in combination with androgen deprivation therapy (ADT) in patients with newly diagnosed metastatic hormone sensitive prostate cancer (PC) and, in combination with docetaxel, in men with non-metastatic castration resistant PC. This phase 2 study assessed the efficacy and safety of DARO as a monotherapy without ADT in patients with non-castrate testosterone (T) levels (≥230 ng/dL). Methods: This was a 24-wk, open-label, randomized study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages, with a max of 4 metastatic lesions) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy &gt;1 y. All patients received DARO 600 mg bid or commercially available LHRH analogue. The primary endpoint is PSA response defined as a ≥ 80% decline at week 24 relative to baseline, in the DARO study arm. The ADT arm is used as an internal control. Secondary endpoints included changes in T levels, safety/tolerability, and quality of life. Results: Among 61 men enrolled, the median (range) age was 72 y (53-86y); 49.2% had metastases; 14.8% and 62.3% had undergone prostatectomy or radiotherapy before study entry. The median (range) of PSA at baseline was 8.9 ng/mL (2.2-333.8). In the DARO arm, the evaluable population with available PSA values at baseline and week 24 consisted of 21 patients. The PSA response rate (&gt;80% PSA decline at wk 24) was 100%, with a median (range) decrease of -99.6% (-94.3, -100) at wk 24 in the DARO arm. Serum T levels increased by a median (range) of 43.4% (5.7-144.0) at wk 24, compared with baseline. In the DARO arm, 45.2% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (19.4%), fatigue (12.9%), and hot flush (12.9%). 3.1% of men experienced SAEs, none of which were drug related. HR-QoL measures and ADT arm results will be presented as internal reference. Conclusions: DARO monotherapy (600 mg bid) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Testosterone level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT02972060 .

Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection.

Androgens may play a role in severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) infection and host responses as the virus is dependent on the androgen-regulated protein transmembrane serine protease 2 for cell entry. Studies have indicated that prostate cancer patients receiving androgen deprivation therapy (ADT) are at reduced risk of SARS-CoV-2 infection and serious complications compared with patients without ADT, but data are inconsistent. A total of 655 prostate cancer patients who were under surveillance at two urology departments in Sweden on April 1, 2020 were included in the study as well as 240 patients with benign prostatic hyperplasia (BPH). At follow-up early in 2021, the participants completed a questionnaire containing information about symptoms compatible with coronavirus disease 2019 (COVID-19). Blood samples were also collected for the assessment of SARS-CoV-2 IgG antibodies (SARS-CoV-2 Total; Siemens). We used multivariable logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between ADT and the risk of SARS-CoV-2 infection. The cumulative incidence of SARS-CoV-2 seropositivity was 13.4% among patients receiving ADT and 10.4% among patients without ADT. After adjusting for potential confounders, we observed no differences in symptoms or risk of SARS-CoV-2 infection between patients with and without ADT (OR: 0.98; 95% CI: 0.52-1.85). Higher body mass index, Type 1 diabetes, and prostate cancer severity, defined by high Gleason score (8-10; OR: 2.06; 95% CI: 1.04-4.09) or elevated levels of prostate-specific antigen(>20 µg/l;OR: 2.15; 95% CI: 1.13-4.07) were associated with increased risk of SARS-CoV-2 infection. Overall, the risk of SARS-CoV-2 infection was not higher among men with prostate cancer than among men with BPH. Our results do not support the hypothesis that ADT use in prostate cancer patients reduces the risk or symptom severity of SARS-CoV-2 infection or that prostate cancer patients are at increased risk of COVID-19 compared with men without prostate cancer.

Relugolix: A Review in Advanced Prostate Cancer.

Relugolix (Orgovyx®), an orally active nonpeptide gonadotropin-releasing hormone (GnRH) receptor antagonist that provides rapid testosterone suppression, is indicated in the USA for the treatment of advanced prostate cancer and in the EU for advanced hormone-sensitive prostate cancer. In the pivotal phase III HERO trial in men with advanced prostate cancer, once-daily oral relugolix (with a loading dose on day 1) led to a sustained castration rate over 48weeks of treatment of > 90%, a rate that was non-inferior to that provided by intramuscular leuprolide depot every 3months (with an exploratory analysis further indicating the superiority of relugolix over leuprolide). Relugolix was generally well tolerated, having an adverse event profile that is consistent with testosterone suppression. Furthermore, there is evidence that relugolix may be associated with a lower risk of major adverse cardiac events compared with leuprolide. With the ability to provide the rapid testosterone suppression (with no initial surge in testosterone upon treatment initiation) combined with the benefits of oral administration and potentially improved cardiac safety, relugolix presents a valuable treatment option for men with advanced prostate cancer where androgen deprivation therapy is indicated.

PSOR9 Presentation Time: 12:10 PM: Utilization of Brachytherapy Boost in Men with Unfavorable Intermediate Risk Prostate Cancer Treated with Radiation Plus Androgen Deprivation Therapy

<h3>Purpose</h3> Randomized data has shown a lower risk of recurrence with the addition of a brachytherapy (BT) boost in men with intermediate- and high-risk prostate cancer treated with external beam radiotherapy (EBRT) and concomitant androgen deprivation therapy (ADT). The inclusion of ADT with BT-based dose escalation is controversial, and professional guidelines support adding or excluding ADT for men with unfavorable intermediate risk prostate cancer treated with EBRT plus a BT boost. However, inclusion of ADT in men with intermediate risk prostate cancer may become more routine after results from RTOG 0815, and its impact on BT utilization in this population is unclear. Herein, we investigate the landscape of BT boost utilization in men with unfavorable intermediate risk prostate treated with EBRT and ADT in the United States. <h3>Materials and Methods</h3> Men ≥ 18 years diagnosed with clinical stage T1-2N0M0, PSA < 20, and Gleason grade group 3 prostate cancer between 2004-2017 were analyzed from the National Cancer Database. Those missing risk-stratification or treatment data were excluded. Eligible patients were grouped into the following cohorts based on primary radiation treatment modality: (i) EBRT alone or (ii) EBRT plus BT boost. EBRT monotherapy group received conventionally fractionated (1.8-2.0 Gy per fraction) ≥ 74 Gy or moderately hypofractionated (2.5-3.0 Gy per fraction) ≥ 60 Gy. EBRT plus BT boost group received conventionally fractionated ≥ 45 Gy or moderately hypofractionated ≥ 37.5 Gy, and either LDR or HDR BT. All patients received concomitant ADT. Cochran-Armitage was used to evaluate radiation modality treatment trends over time, and multivariable logistic regression was used to identify sociodemographic predictors of treatment. <h3>Results</h3> Among the eligible cohort, 46,490 (82%) were treated with EBRT alone and 10,236 (18%) were treated with EBRT plus BT boost. Median (range) age was 70 years (38-90). Between 2004 to 2017, there was a significant decline in annual use of a BT boost, from 24.5% in 2004 to 16.4% in 2017 (p<0.001). On MVA, Black race (adjusted OR 0.85, 95% CI 0.79-0.90, P<.0001), Medicaid insurance (aOR 0.67, 95% CI 0.57-0.78, P<.0001), and Charlson-Deyo comorbidity index > 1 (aOR 0.78, 95% CI 0.61-0.99, P=0.04) were associated with decreased odds of receiving a BT boost. Private insurance (aOR 1.11, 95% CI 1.05-1.18, P=.001), treatment at an academic institution (aOR 1.25, 95% CI 1.12-1.39, p<.0001), and Charlson-Deyo comorbidity index 0 (aOR 1.07, 95% CI 1.00-1.15, P=.04) were associated with increased odds of receiving a BT boost. <h3>Conclusions</h3> For men with unfavorable intermediate risk prostate cancer, utilization of a BT boost has significantly declined in the United States over the past two decades. Black and uninsured men have been at particularly high risk of undertreatment. Future studies aimed at identifying which men with intermediate-risk prostate cancer (e.g. based on genomic classifier or magnetic resonance imaging) derive the greatest oncologic benefit from a BT boost with EBRT and ADT is warranted to appropriately identify those who may be at risk of undertreatment with its exclusion. Additionally, future initiatives are needed to close the disparity gap in access and/or delivery of this efficacious treatment for Black and uninsured men, an overall undertreated population.

Case - Leuprolide acetate-induced necrotic skin ulceration.

Androgen deprivation therapy (ADT) has become a well-established modality in the management of locally advanced and metastatic prostate cancer.1 Leuprolide acetate, a synthetically derived gonadotropin-releasing hormone receptor (GnRHR) agonist, is commonly used for ADT in men.2 Despite proven effectiveness, the administration of GnRHR agonists is associated with common adverse reactions, such as impotence, hot flashes, and fatigue. Injection site reactions have also been documented, however, are infrequent, with the most common being localized pain.3,4 Here, we report a case of necrotic skin ulceration following multiple administrations of intramuscular leuprolide acetate.

Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) vs. Dose Escalated Radiation Therapy and Enhanced ADT with TAK-700 for Men with High-Risk Prostate Cancer (NRG Oncology/RTOG 1115)

<h3>Purpose/Objective(s)</h3> RTOG 1115 was a randomized phase III trial evaluating the addition of orteronel (TAK-700), a novel CYP17A1 inhibitor, to dose escalated radiation plus ADT in men with high risk, localized prostate cancer. Originally designed to evaluate overall survival, the trial was halted early due to discontinuation of orteronel development in prostate cancer. We report here the initial primary endpoint analysis. <h3>Materials/Methods</h3> The study was designed to enroll 900 men with high-risk prostate cancer (Gleason 9-10, PSA > 20, or clinical stage T2 or higher with Gleason ≥ 8). Ultimately, 238 patients were enrolled (May 2012-Sept 2014), and randomized 1:1 to receive standard therapy (Arm A), or standard therapy plus two years of twice daily orteronel (Arm B). Radiation therapy entailed dose-escalated external beam radiation (EBRT) to the prostate and pelvis to 45 Gy in 25 fractions, followed by a boost to 79.2 Gy using EBRT or either HDR or LDR. The analysis plan was reframed around detecting a reduction in rate of a composite biochemical failure endpoint (Phoenix biochemical failure, local/regional or distant disease, or salvage ADT). With 238 patients enrolled and followed, the study would have 70% power to detect a 40% decrease in the composite failure primary endpoint after 70 events had occurred. <h3>Results</h3> 231 patients were evaluable for efficacy and toxicity, 115 in Arm A and 116 in Arm B, and median follow up was 6.2 years. Grade 3 adverse events were observed in 35% and 60% of men in Arm A and B, respectively, with most common being urinary or gastrointestinal disturbance. Time to grade 3 adverse event was significantly faster in Arm B (log rank P value < 0.001). There were four deaths due to adverse events, three of which were in Arm A, and all were deemed unlikely related to treatment. Notably, only 29% of men in Arm B received 80% or more of the planned dose of orteronel due to a variety of factors that impacted drug tolerability. With respect to the primary outcome, patients did well overall with 6-year failure rates of 22.5% and 16.1%, respectively, in Arms A and B (hazard ratio [HR] 0.83, 95% CI 0.47-1.48). By Phoenix definition, PSA failure was only 18.4% and 12.1% in Arms A and B through 6 years. Distant failure occurred in 10.0% and 4.0% of patients (HR 0.71, 95% CI 0.29-1.75). Quality of life outcomes will be reported separately. While all efficacy trends favored the experimental arm, due to the small number of patients and events none of the differences between arms achieved statistical significance. <h3>Conclusion</h3> The addition of orteronel to dose escalated RT and ADT did not result in statistically significant improvement in efficacy outcomes, although results were limited by early termination of accrual and impaired drug tolerability. Intensification of hormonal therapy with better tolerated novel agents remains an appealing strategy for the treatment of high-risk localized prostate cancer.

Open-label study of androgen receptor inhibition with darolutamide plus androgen-deprivation therapy (ADT) versus ADT in men with metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC).

TPS5111 Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor (ARI) that significantly improved metastasis-free survival by ̃2 years and reduced the risk of death by 31% vs placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Darolutamide has a favorable safety and tolerability profile, with only ≤2% difference vs placebo for most adverse events (AEs) of interest (falls, fractures, hypertension, mental impairment). Fatigue was the only AE with &gt; 10% incidence in the darolutamide arm (13.2%; placebo, 8.3%). Darolutamide has shown lower blood–brain barrier penetration than other ARIs in preclinical models (supported by human neuroimaging studies), which may lead to a lower risk of central nervous system-related AEs and has a low potential for drug–drug interactions. For patients with metastatic hormone-sensitive prostate cancer (mHSPC), the combination of darolutamide and ADT is expected to offer a favorable benefit–risk profile. ARASEC will evaluate the efficacy and safety of darolutamide plus ADT in mHSPC in the US (NCT05059236) and complement the data in the ongoing ARANOTE study (NCT04736199). Methods: ARASEC is a US-based, phase 2, open-label, single-arm study with an external control arm. Eligible patients will have confirmed adenocarcinoma of the prostate, radiologic evidence of metastatic disease by conventional imaging, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Patients with mHSPC will receive darolutamide 600 mg twice daily plus ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). The control arm for ARASEC will be derived from the 393 patients with mHSPC treated with ADT alone in the CHAARTED trial. Patients in the active arm will be matched 1:1 to patients in the control arm using important baseline characteristics such as age, ECOG PS, extent of disease defined as low or high volume according to CHAARTED, and presence of bone and visceral metastases. Study duration was defined as the time from the first patient’s first visit until either the event count threshold triggering the primary endpoint analysis has been met or all patients have been followed for ≥2 years after enrollment, whichever occurs later. The primary endpoint is progression-free survival (PFS), defined in CHAARTED as the time from enrollment to prostate-specific antigen (PSA) progression, clinical progression (including radiological or symptomatic progression or clinical deterioration), or death, whichever occurs first. Secondary endpoints are overall survival, radiographic PFS, time to CRPC, complete PSA response rate at 6 months, and safety. Patient recruitment is in progress. Clinical trial information: NCT05059236.

Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: Meta-analysis of individual participant data from randomized trials.

5070 Background: Adding docetaxel to androgen deprivation therapy(ADT) improves survival in metastatic, hormone-sensitive prostate cancer (mHSPC), but uncertainty remains about who benefits most. To investigate this thoroughly and reliably, the STOPCAP M1 collaborationconducted a meta-analysis of individual participant data (IPD) from relevant trials. Methods: Methods were included in a registered protocol ( CRD42019140591 ). Updated IPD from the GETUG-15, CHAARTED and STAMPEDE trials were harmonised and checked. The main outcomes were overall survival (OS), progression-free survival (PFS) and failure-free survival (FFS). Overall pooled effects were estimated using intention-to-treat, 2-stage, fixed-effect meta-analysis, adjusted for age, PSA, Gleason sum score, performance status, and timing of metastatic disease (missing covariate values imputed), with 1-stage and random-effects sensitivity analyses. We assessed subgroup effects using 2-stage, fixed-effect meta-analysis of within-trial interactions, adjusted for the same covariates. We based these on PFS to maximise power, and OS whenever interactions were found. To explore multiple subgroup interactions, and to derive subgroup-specific absolute treatment effects, we used 1-stage, flexible parametric modelling and standardisation. Results: We obtained IPD for all 2261 men randomised, with median FU of 6 years (all patients). There were clear relative benefits of docetaxel on OS (HR = 0.79, 95% CI 0.70 to 0.88, p&lt;0.0001), PFS (HR = 0.70, 95% CI 0.63 to 0.77, p&lt;0.0001) and FFS (HR = 0.64, 95% CI 0.58 to 0.71, p&lt;0.0001). With evidence of non-proportional hazards, we also estimated 5-year absolute differences: OS 10% (95% CI 6 to 15%), PFS 9% (95% CI 5 to 13%) and FFS 9% (95% CI 6 to 12%). The relative effect of docetaxel on PFS differed by volume of metastases (interaction p=0.027; high volume HR = 0.60, 95% CI 0.52 to 0.68; low volume HR = 0.78, 95% CI 0.64 to 0.94), and timing of metastatic disease (interaction p=0.077; synchronous HR = 0.67, 95% CI 0.60 to 0.75; metachronous HR = 0.89, 95% CI 0.67 to 1.18). OS results were similar. When metastatic disease volume and timing were combined, docetaxel appeared to improve PFS and OS for all men, except those with low volume, metachronous disease (Table). Conclusions: This IPD meta-analysis provides the most detailed assessment of the effects of docetaxel for mHSPC, and suggests that men with low volume, metachronous disease should be managed differently to those with other types of metastatic disease. [Table: see text]

A randomized phase Ib/II study of intermittent androgen deprivation therapy plus nivolumab with or without interleukin-8 blockade in men with hormone-sensitive prostate cancer (MAGIC-8).

5082 Background: Immunotherapy has limited efficacy in castration-resistant prostate cancer. Androgen deprivation therapy (ADT) has significant immunomodulatory effects and initially induces a complex immune infiltrate before castration-resistance develops. However, ADT also recruits immunosuppressive myeloid cells to the tumor microenvironment by increasing interleukin-8 (IL-8). We conducted a phase Ib/II clinical trial of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC). We hypothesized that anti-PD-1 (nivolumab) +/- anti-IL-8 (BMS-986253) given at the time of castration could induce anti-tumor immune responses and decrease disease progression. Methods: MAGIC-8 was a multicenter, phase Ib/II study evaluating nivolumab +/- BMS-986253 combined with a short course of degarelix acetate in patients with recurrent CSPC and rapid PSA doubling time (≤ 12 mos). In the Phase Ib portion, patients were treated with nivolumab (480mg Q4W) for 8 wks followed by nivolumab plus degarelix for an additional 16 wks. In the phase II portion, patients were randomized 1:2 to nivolumab + degarelix (Arm A) versus nivolumab + BMS-986253 (2400mg Q2W) + degarelix (Arm B). The primary endpoints were PSA recurrence at 10 mos following randomization and safety. Key secondary endpoints included biochemical recurrence-free survival (bPFS), time to recovery of testosterone (&gt; 150ng/dl), and bPFS after recovery of testosterone. Results: Between October 16, 2019 and March 9, 2021, 59 patients were enrolled. The first 15 patients were treated on Arm A followed by 1:2 randomization to Arm A (N = 15) versus Arm B (N = 29). Median follow up was 11.6 mos at the data cutoff (1/24/22). Patients treated on Arm A had a significantly lower rate of PSA relapse (17.39%) at 10 mos compared to historical controls (p = &lt; 0.001), including a subgroup of patients (6.67%) with recovery of testosterone and no PSA relapse at &gt; 2 years of follow up. Median time-to-recovery of testosterone was 12.7 mos, median bPFS was 14.0 mos and median bPFS after recovery of testosterone was 5.5 mos. In Arm B, there was no difference in PSA relapse at 10 mos (35%, p = 0.09), median time-to-recovery of testosterone, median bPFS and median bPFS after recovery of testosterone compared to historical controls. Treatment in both arms was well tolerated with a lower rate of grade 3-4 treatment-related adverse events in Arm B compared to Arm A (3.5% vs 12.9%). Conclusions: A short course of ADT plus nivolumab may decrease the rate of PSA relapse and lead to durable long-term responses after recovery of testosterone in a subset of patients. These data support further evaluation of combining nivolumab with ADT in CSPC. Although the addition of BMS-986253 did not improve rate of PSA relapse, we observed significantly less toxicity with the addition of IL-8 inhibition. Clinical trial information: NCT03689699.

Assessing the impact of brachytherapy boost and androgen deprivation therapy on survival outcomes for patients with unfavorable intermediate-risk prostate cancer patients treated with external beam radiotherapy

BACKGROUNDCurrent recommendations regarding radiotherapy treatment for unfavorable intermediate-risk prostate cancer (UIR-PCa) include external beam radiotherapy (EBRT) ± brachytherapy boost (BT) ± androgen deprivation therapy (ADT). The ideal radiotherapy treatment approach for UIR-PCa has not been well-defined. We hypothesized that EBRT+BT±ADT is associated with improved overall survival (OS) relative to EBRT±ADT in men with UIR-PCa. MATERIALS AND METHODSThe National Cancer Database (NCDB) was used to retrospectively identify 32,246 men diagnosed between 2004 and 2015 with UIR-PCa who received EBRT (n = 13,265), EBRT+ADT (n = 13,123), EBRT+BT (n = 3440), or EBRT+BT+ADT (n = 2418). OS was the primary outcome. Inverse probability of treatment weighting was used to adjust for covariable imbalances and weight-adjusted multivariable analysis using Cox regression modeling was used to compare OS hazard ratios. RESULTSMedian follow-up was 60 months (range: 3–168 months). EBRT+ADT correlated with improved OS relative to EBRT alone on multivariable analysis (Hazard Ratio (HR): 0.92, [95% Confidence Interval: 0.87–0.98], p = 0.005). Compared to EBRT+ADT, EBRT+BT (HR: 0.77 [0.69–0.85], p = 3 × 10−7) and EBRT+BT+ADT (HR: 0.75 [0.67–0.83], p = 6 × 10−8) were associated with improved OS. Eight-years OS for the EBRT+ADT versus EBRT+BT+ADT was 70% and 78% (p < 0.0001), which is similar to historical clinical trials (ASCENDE-RT 9-year OS: 74% vs. 78%, p = 0.29). Relative to EBRT+BT, EBRT+BT+ADT was not associated with improved OS (HR: 0.99 [0.87–1.11], p = 0.82). CONCLUSIONSIn a large retrospective cohort, the addition of brachytherapy to EBRT correlated with improved survival in men with UIR-PCa. Men receiving EBRT+ADT+BT had improved OS relative to EBRT+ADT. The addition of ADT to EBRT, but not to EBRT+BT, correlated with improved OS.

Characteristics of Patients in SPCG-15—A Randomized Trial Comparing Radical Prostatectomy with Primary Radiotherapy plus Androgen Deprivation Therapy in Men with Locally Advanced Prostate Cancer

BackgroundThere is no high-grade evidence for surgery as primary treatment for locally advanced prostate cancer. The SPCG-15 study is the first randomized trial comparing surgical treatment with radiotherapy. ObjectiveTo describe the baseline characteristics of the first 600 randomized men in the SPCG-15 study. The study will compare mortality and functional outcomes. Design, setting, and participantsThis study is a Scandinavian prospective, open, multicenter phase III randomized clinical trial aiming to randomize 1200 men. InterventionRadical prostatectomy with or without consecutive radiotherapy (experimental) and radiotherapy with neoadjuvant androgen deprivation therapy (standard of care). Outcome measurements and statistical analysisCause-specific survival, metastasis-free survival, overall survival, and patient-reported bowel function, sexual health, and lower urinary tract symptoms were measured. Results and limitationsThe distribution of characteristics was similar in the two study arms. The median age was 67 yr (range 45–75 yr). Among the operated men, 36% had pT3a stage of disease and 39% had pT3b stage. International Society of Urological Pathology grades 2, 3, 4, and 5 were prevalent in 21%, 35%, 7%, and 27%, respectively. Half of the men (51%) in the surgery arm had no positive lymph nodes. The main limitation is the pragmatic design comparing the best available practice at each study site leading to heterogeneity of treatment regimens within the study arms. ConclusionsWe have proved that randomization between surgery and radiotherapy for locally advanced prostate cancer is feasible. The characteristics of the study population demonstrate a high prevalence of advanced disease, well-balanced comparison groups, and a demography mirroring the Scandinavian population of men with prostate cancer at large. Patient summaryThis study, which has recruited >600 men, compares radiotherapy with surgery for prostate cancer, and an analysis at the time of randomization indicates that the study will be informative and generalizable to most men with locally advanced but not metastasized prostate cancer.

Outcome of primary androgen deprivation therapy in super-elderly men with localized high-risk prostate cancer.

The purpose of this study is to provide certain data on clinical outcome of primary androgen deprivation therapy in men over 80 years of age with localized high-risk prostate cancer. This study included 54 Japanese super-elderly men with high-risk prostate cancer treated with primary androgen deprivation therapy between 2005 and 2015. The median overall survival was 9.1 years (95% confidence interval, 8.1-10.1) and no patient died from prostate cancer. Overall, 51.9% of patients experienced any grade of adverse events following androgen deprivation therapy. Associations between clinicopathological factors including comorbidity count at initial diagnosis and overall survival were investigated. On multivariate analysis, only comorbidity count at initial diagnosis [≥2 vs. ≤1; hazard ratio, 5.34 (95% confidence interval, 1.55-18.49); P = 0.003] was an independent risk factor for overall survival. Our findings suggest that comorbidity count at initial diagnosis is robustly prognostic for overall survival. For super-elderly men with localized high-risk prostate cancer, comorbidity count at initial diagnosis should be emphasized when deciding whether primary androgen deprivation therapy is necessary or not.

Editorial Comment to Comparative oncological outcomes after radical prostatectomy or external beam radiation therapy plus androgen deprivation therapy in men with clinical T3b prostate cancer.

Editorial Comment to Comparative oncological outcomes after radical prostatectomy or external beam radiation therapy plus androgen deprivation therapy in men with clinical T3b prostate cancer.

Leuprolide Acetate and QTc Interval in Gender-Diverse Youth.

Puberty suppression is a standard of care for gender-affirming therapy in gender-diverse youth. Leuprolide acetate is a gonadotropin-releasing hormone agonist (GnRHa) commonly used for pubertal suppression. There are concerns that GnRHa agents prolong the rate-corrected QT interval (QTc) when used as androgen deprivation therapy in management of prostate cancer; however, there is a paucity of literature regarding the effect of leuprolide acetate on QTc intervals in gender-diverse youth. To determine the proportion of gender-diverse youth with QTc prolongation on leuprolide acetate therapy. A retrospective chart review of gender-diverse youth initiated on leuprolide acetate between July 1, 2018 and December 31, 2019 was conducted at a tertiary care pediatric hospital in Alberta, Canada. Youth aged 9-18 years were included if a 12-lead electrocardiogram was completed after initiating leuprolide acetate. The proportion of adolescents with clinically significant QTc prolongation was assessed, defined as QTc >460 milliseconds (ms). Thirty-three pubertal youth were included. The cohort had a mean age of 13.7 years (standard deviation [SD] 2.1) and 69.7% identified as male (assigned female at birth). The mean post-leuprolide acetate QTc was 415 ms (SD 27, range 372-455). Twenty-two (66.7%) of youth were prescribed concomitant medications, including QTc-prolonging medications in 15.2%. None of the 33 youth on leuprolide acetate had QTc prolongation. Only 24.2% patients had a borderline QTc (QTc 440-460 ms). No gender-diverse youth on leuprolide acetate demonstrated clinically significant QTc prolongation.