Androgen Deprivation Therapy Group Research Articles

Insulin resistance during androgen deprivation therapy in men with prostate cancer.

Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. The ADT & Metabolism Study was a single-center, 24-week, prospective observational study that enrolled ADT-naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n=42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non-ADT group, n=23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], -2.10 to 4.43; p=.47) or skeletal muscle (-3.2; 95% CI, -7.07 to 0.66; p=.10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non-ADT group. Men undergoing ADT gained 3.7 kg of fat mass. In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short-term ADT.

Evaluating the Effects of Prostate Radiotherapy Intensified with Pelvic Nodal Radiotherapy and Androgen Deprivation Therapy on Myelosuppression: Single-Institution Experience.

Prostate cancer (PCa) management commonly involves the utilization of prostate radiotherapy (PRT), pelvic nodal radiotherapy (PNRT), and androgen deprivation therapy (ADT). However, the potential association of these treatment modalities with bone marrow (BM) suppression remains inadequately reported in the existing literature. This study is designed to comprehensively evaluate the risk of myelosuppression associated with PRT, shedding light on an aspect that has been underrepresented in prior research. We conducted a retrospective analysis of 600 patients with prostate cancer (PCa) treated with prostate radiotherapy (PRT) at a single oncology center between 2007 and 2017. Patients were categorized into four cohorts: PRT alone (n = 149), PRT + ADT, (n = 91), PRT + PNRT (n = 39), and PRT + PNRT + ADT (n = 321). To assess the risk of myelosuppression, we scrutinized specific blood parameters, such as hemoglobin (HGB), white blood cells (WBCs), neutrophils (NEUT), lymphocytes (LYM), and platelets (PLT) at baseline, mid-treatment (mRT), immediately post-RT (pRT), 1 month post-RT (1M-pRT), and 1 year post-RT (1Y-pRT). The inter-cohort statistical significance was evaluated with further stratification based on the utilized RT technique {3D conformal radiotherapy (3D-CRT), and intensity-modulated radiation therapy (IMRT)}. Significant statistical differences at baseline were observed in HGB and LYM values among all cohorts (p < 0.05). Patients in the PRT + PNRT + ADT cohort had significantly lower HGB at baseline and 1M-pRT. In patients undergoing ADT, BMS had a significant impact at 1M-pRT {odds ratio (OR) 9.1; 95% Confidence Interval (CI) 4.8-17.1} and at 1Y-pRT (OR 2.84; CI 1.14-7.08). The use of 3D-CRT was linked to reduced HGB levels in the PRT + PNRT + ADT group at 1 month pRT (p = 0.015). Similarly, PNRT significantly impacted BMS at 1M-pRT (OR 6.7; CI 2.6-17.2). PNRT increased the odds of decreased WBC counts at 1Y-pRT (OR 6.83; CI: 1.02-45.82). Treatment with any RT techniques (3D-CRT or IMRT), particularly in the PRT + PNRT and PRT + PNRT + ADT groups, significantly increased the odds of low LYM counts at all time points except immediately pRT (p < 0.05). Furthermore, NEUT counts were considerably lower at 1M-pRT (p < 0.05) in the PRT + PNRT + ADT group. PLT counts were significantly decreased by PRT + PNRT + ADT at mRT (OR 2.57; 95% CI: 1.42-4.66) but were not significantly impacted by the RT technique. Treatment with PRT, ADT, PNRT, and 3D-CRT is associated with BMS. Despite this statistically significant risk, no patient required additional interventions to manage the outcome. While its clinical impact appears limited, its importance cannot be underestimated in the context of increased integration of novel systemic agents with myelosuppressive properties. Longer follow-up should be considered in future studies.

Changes in the treatment landscape of metastatic hormone-sensitive prostate cancer: A multicenter study.

118 Background: A multicenter database was utilized to examine the current treatment landscape and clinical outcomes among patients with metastatic hormone-sensitive prostate cancer (mHSPC) following approval of upfront androgen receptor signaling inhibitors (ARSIs). Methods: We retrospectively analyzed patients with mHSPC who commenced treatment between February 2018 and June 2023. The Kaplan–Meier method was used to assess oncological outcomes, including time to castration-resistant prostate cancer (CRPC), progression-free survival 2 (PFS2, duration from initial treatment to tumor progression during second-line treatment), cancer-specific survival (CSS), and overall survival (OS). Cox regression analyses were performed to determine the impact of treatment choices on oncological outcomes. In addition, the incidence rate of adverse events was assessed. Results: In total, 829 patients were analyzed; 42.5% received ARSIs with androgen deprivation therapy (ADT), 44.0% received combined androgen blockade (CAB), and 13.5% received ADT alone. Analysis of annual treatment choice trends revealed an increasing preference for ARSIs with ADT. Kaplan–Meier curves and multivariate Cox regression analyses indicated higher rates of CRPC and shorter PFS2 in patients treated with CAB versus ARSIs with ADT. By contrast, CSS and OS were not significantly different between the ARSI with ADT group and the CAB group. Grade 3–4 adverse events occurred in 1.9% of patients receiving CAB and 6.0% of those receiving ARSIs with ADT. Conclusions: For patients with mHSPC, initial treatment with ARSIs in combination with ADT resulted in a longer time to CRPC and longer PFS2 compared to CAB. Although CAB and ADT alone were associated with fewer adverse events, ARSIs with ADT should be considered a first-line treatment option given its superior oncological outcomes.

Changes in the treatment landscape of metastatic hormone-sensitive prostate cancer following approval of upfront androgen receptor signaling inhibitors: A multicenter study.

A multicenter database was utilized to examine the current treatment landscape and clinical outcomes among patients with metastatic hormone-sensitive prostate cancer (mHSPC) following approval of upfront androgen receptor signaling inhibitors (ARSIs). We retrospectively analyzed patients with mHSPC who commenced treatment between February 2018 and June 2023. The Kaplan-Meier method was used to assess oncological outcomes, including time to castration-resistant prostate cancer (CRPC), progression-free survival 2 (PFS2, duration from initial treatment to tumor progression during second-line treatment), cancer-specific survival (CSS), and overall survival (OS). Cox regression analyses were performed to determine the impact of treatment choices on oncological outcomes. In addition, the incidence rate of adverse events was assessed. In total, 829 patients were analyzed; 42.5% received ARSIs with androgen deprivation therapy (ADT), 44.0% received combined androgen blockade (CAB), and 13.5% received ADT alone. Kaplan-Meier curves and multivariate Cox regression analyses indicated higher rates of CRPC and shorter PFS2 in patients treated with CAB versus ARSIs with ADT. By contrast, CSS and OS were not significantly different between the ARSI with ADT group and the CAB group. Grades 3-4 adverse events occurred in 1.9% of patients receiving CAB and 6.0% of those receiving ARSIs with ADT. Initial treatment with ARSIs in combination with ADT resulted in a longer time to CRPC and longer PFS2 compared to CAB. Although CAB and ADT alone were associated with fewer adverse events, ARSIs with ADT should be considered a first-line treatment option given its superior oncological outcomes.

Impact of Androgen Deprivation Therapy on Lumbar Spine Bone Health Using Quantitative Computed Tomography in a Propensity-Matched Cohort of Patients With Prostate Cancer

Purpose: Fragility fracture risk in patients with prostate cancer is an important issue. The purpose of this study was to accurately assess the impact of androgen deprivation therapy on lumbar spine bone loss using quantitative computed tomography in a propensity-matched cohort of patients with prostate cancer. Materials and Methods: Eighty-one patients with prostate cancer who underwent androgen deprivation therapy for 1 year were included. Thirty-nine of these patients were successfully propensity-matched with 39 of 68 patients from a control group who underwent robot-assisted radical prostatectomy without androgen deprivation therapy. Volumetric bone mineral density of trabecular bone in each vertebral body (L1-L4) was measured using quantitative computed tomography during staging and at 1 year after commencing treatment. The change in mean lumbar volumetric bone mineral density (L1-L4) was then calculated. Results: Propensity score matching successfully achieved comparable baseline patient characteristics and radiological parameters between the androgen deprivation therapy and control groups. In the androgen deprivation therapy group, the decrease in lumbar volumetric bone mineral density (L1-L4) was significantly greater with confirmed testosterone deficiency (−17.9 ± 12.0%) compared with the control group (−8.5 ± 10.8%, P &lt; .001). Conclusions: This study observed a 17.9% reduction in volumetric lumbar bone mineral density (g/cm3) after 1 year of androgen deprivation therapy, exceeding previously reported values (g/cm2) obtained using dual-energy X-ray absorptiometry. The potential overestimation of lumbar spine bone mineral density measured by dual-energy X-ray absorptiometry in older patients with prostate cancer because of concomitant lumbar degenerative disease is a possible reason for this discrepancy. Androgen deprivation therapy may decrease vertebral bone mass and increase the risk of vertebral fractures more than urologists realize.

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Abstract 973: Plasma androgen receptor (AR) copy number gain at progression in patients randomized in the STAMPEDE phase 3 abiraterone acetate, prednisolone (AAP) and enzalutamide (ENZ) trial: An ancillary biomarker study

Abstract Addition of ENZ or AAP to androgen deprivation therapy (ADT) as first-line treatment for advanced prostate cancer improves survival compared to ADT alone. Genomic alterations in AR associate with resistance to ENZ/AAP when started for castration-resistant prostate cancer (CRPC). We aimed to test whether early use of AAP/ENZ altered the incidence of AR alterations at progression. Between July 2014 and March 2016, 1976 patients with metastatic or high-risk locally advanced prostate cancer were randomized to ADT or ADT+ENZ+AAP in the STAMPEDE trial (NCT00268476). Consenting patients were given the option to donate blood for the ancillary biomarker study at trial-defined progression and prior to start of the next line of treatment. We focused on patients who progressed within 4 years from the end of recruitment (early progressors), as these patients represent the greatest unmet need. We obtained plasma DNA at emergence of CRPC from 115 early progressors (ADT n=63, ADT+ENZ+AAP n=52). We performed liquid biopsy-focused, custom, high-coverage targeted enrichment sequencing (PCF-SELECT, Orlando et al, NAR Cancer 2022). We used a bespoke computational pipeline, leveraging allelic imbalance and fragmentome analysis, to detect circulating tumor DNA (ctDNA) in plasma samples and copy number changes. Of 108 samples that passed quality control, 94 were positive for tumor (ADT n=52, ADT+AAP+ENZ n=42). The detection rate and ctDNA fractions were similar between the two treatment groups [ADT: 86.7% (52/60), mean ctDNA fraction 0.18; ADT+ENZ+AAP: 87.5% (42/48), mean ctDNA fraction 0.21; p=0.34]. The proportion of plasma with detectable ctDNA and AR gain was significantly higher with ADT+AAP+ENZ vs ADT alone (15/42, 35.7% vs 8/52, 15.4%, p=0.03). We then implemented the same approach on plasma collected from patients progressing on ENZ started for metastatic CRPC in a prospective Phase 3b trial (PRESIDE, NCT02288247): we confirmed a high prevalence of AR gain in plasma samples with detectable ctDNA (47.7%, 95% CI 38.8-54.9) in the CRPC setting. Significant copy number aberrations in relevant prostate cancer-related genes/pathways (deletions of TP53, RB1, PTEN or DNA repair genes, or gain of PI3K/AKT1) were identified in 9 out of 42 evaluable samples in the ADT group and 18 out of 38 evaluable samples in the ADT+ENZ+AAP group (21.4% vs 47.4%, p=0.014). Treatment with ADT+ENZ+AAP increases detection of plasma AR gain at emergences of CRPC in early progressors compared to ADT alone. Detection of plasma AR gain increases at progression on ADT+ENZ regardless of the treatment setting. The impact of early use of ENZ/AAP on the detection of copy number aberrations, especially homozygous deletions, in other prostate cancer-related genes in plasma requires further investigation. Citation Format: Gianmarco Leone, Francesco Orlando, Suparna Thakali, Sharanpreet Lall, Daniel Wetterskog, Anna Wingate, Noel W. Clarke, Nicholas D. James, Francesca Demichelis, Gerhardt Attard. Plasma androgen receptor (AR) copy number gain at progression in patients randomized in the STAMPEDE phase 3 abiraterone acetate, prednisolone (AAP) and enzalutamide (ENZ) trial: An ancillary biomarker study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 973.

Secondary Cancer after Androgen Deprivation Therapy in Prostate Cancer: A Nationwide Study.

Androgen signaling is associated with various secondary cancer, which could be promising for potential treatment using androgen deprivation therapy (ADT). This study investigated whether ADT use was associated with secondary cancers other than prostate cancer in a nationwide population-based cohort. A total, 278,434 men with newly diagnosed prostate cancer between January 1, 2002 and December 31, 2017 were identified. After applying the exclusion criteria, 170,416 men were enrolled. The study cohort was divided into ADT and non-ADT groups by individual matching followed by propensity score matching (PSM). Study outcomes were incidence of all male cancers. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of events. During a median follow-up of 4.5 years, a total of 11,059 deaths (6,329 in the ADT group and 4,730 in the non-ADT group) after PSM were found. After PSM, the overall all-cause of secondary cancer incidence risk of the ADT group was higher than that of the non-ADT group (HR: 1.312, 95% CI: 1.23-1.36; adjusted HR: 1.344, 95% CI: 1.29-1.40). The ADT group showed higher risk of overall brain and other central nervous system (CNS) cancer-specific incidence than the non-ADT group (adjusted HR: 1.648, 95% CI: 1.21-2.24). The ADT group showed lower risks of overall cancer-specific incidence for stomach, colon/rectum, liver/inflammatory bowel disease (IBD), gall bladder/extrahepatic bile duct, lung, bladder, and kidney cancers than the non-ADT group. When the duration of ADT was more than 2 years of ADT, the ADT group showed higher risk of cancer-specific incidence for brain and other CNS cancers but lower risk of cancer-specific incidence for liver/IBD and lung cancers than the non-ADT group. This study demonstrates that ADT could affect cancer-specific incidence for various cancers.

Role of Positive Biopsy Core Ratio in Prostate Cancer Patients.

The percentage of positive cores (PPC) is increasingly recognized as a prognostic factor in prostate cancer. However, the usefulness of PPC for patients undergoing androgen deprivation therapy (ADT) and high-risk group has not been adequately studied. A retrospective analysis was conducted of 255 patients who underwent prostate biopsy (all-case group). We examined the efficacy of PPC as a prognostic biomarker. Eighty-nine patients were treated with ADT alone (ADT group), and 107 patients were classified as high-risk (high-risk group). The median duration of follow-up was 112.4 months, 85.3 months, and 110.0 months for the all-case, ADT, and high-risk groups, respectively. Patients with PPC >60% had significantly shorter prostate cancer-specific survival (CSS) and castration-resistant prostate cancer-free survival (CFS) in the all-case and ADT groups. In the high-risk group, patients with PPC >60% had shorter CFS but no difference in CSS. Multivariate analysis showed that significant independent predictors of prostate CSS were the presence of metastasis at diagnosis and PPC >60% in the all-case and ADT groups. PPC may be a prognostic factor in ADT treated and high-risk prostate patients.

Antihormonal-Treatment Status Affects 68Ga-PSMA-HBED-CC PET Biodistribution in Patients with Prostate Cancer.

Androgen deprivation therapy (ADT) is known to influence the prostate-specific membrane antigen (PSMA) expression of prostate cancer, potentially complicating the interpretation of PSMA ligand PET findings and affecting PSMA radioligand therapy. However, the impact of ADT on PSMA ligand biodistribution in nontumorous organs is not well understood. Methods: Men (n = 112) with histologically proven prostate cancer who underwent 68Ga-PSMA-HBED-CC (68Ga-PSMA-11) PET/CT between November 2015 and July 2021 at the Medical University Vienna with known ADT status were retrospectively recruited. Fifty-six patients were on gonadotropin-releasing hormone-interfering ADT at the time of imaging (ADT group), whereas 56 patients with no history of ADT served as a control group. Physiologically PSMA-expressing organs (salivary glands, kidneys, liver, and spleen) were delineated, and their uptake was compared according to their data distributions. Multivariate regression analysis assessed the relationship between renal, hepatic, splenic, and salivary gland uptake and the explanatory variables metabolic tumor volume, glomerular filtration rate, and ADT status. Results: ADT was associated with lower levels of PSMA uptake in the kidneys (SUVmean: Δ[ADT - control] = -7.89; 95% CI, -10.73 to -5.04; P < 0.001), liver (SUVpeak: Δ[ADT - control] = -2.3; 95% CI, -5.72 to -0.93; P = 0.003), spleen (SUVpeak: Δ[ADT - control] = -1.27; 95% CI, -3.61 to -0.16; P = 0.033), and salivary glands (SUVmean: Δ[ADT - control] = -1.04; 95% CI, -2.48 to -0.13; P = 0.027). In a multivariate analysis, ADT was found to be associated with lower renal (SUVmean: β = -7.95; 95% CI, -11.06 to -4.84; P < 0.0001), hepatic (SUVpeak: β = -7.85; 95% CI, -11.78 to -3.91; P < 0.0001), splenic (SUVpeak: β = -5.83; 95% CI, -9.95 to -1.7; P = 0.006), and salivary gland (SUVmean: β = -1.47; 95% CI, -2.76 to -0.17; P = 0.027) uptake. A higher glomerular filtration rate was associated with a higher renal SUVmean (β = 0.16; 95% CI, 0.05 to 0.26; P = 0.0034). Conclusion: These findings suggest that ADT systemically modulates PSMA expression, which may have implications for treatment-optimizing and side-effect-minimizing strategies for PSMA radioligand therapies, particularly those using more potent 225Ac-labeled PSMA conjugates.

Changes in the gut microbial profile during long-term androgen deprivation therapy for prostate cancer.

Recent studies have highlighted the association between androgen deprivation therapy (ADT) and the gut microbiota in prostate cancer. However, the impact of long-term ADT remains to be explored. To examine changes in the gut microbial profile from short-term (a median of 7 months), and middle-term (a median of 18 months) to long-term ADT (>33 months), 16S rRNA data from56 fecal samples were reanalyzed. Additionally, a two-sample Mendelian randomization was employed to investigate the relationships between particular microbial signatures and prostate cancer as well as testosterone levels. In contrast to the short- and middle-term ADT groups, the long-term ADT group had significant changes in alpha and beta diversity. In particular, the relative abundance of generasuch as Catenibacterium and Holdemanella decreased in the long-term ADTgroup, whereas the opportunistic bacterium (Erysipelatoclostridium) and Ruminococcus gnavus showed increased abundance over ADT time. Moreover, atwo-sample Mendelian randomization analysis revealed the negative associations between genetically predicated genera Coprobacter, Ruminococcaceae UCG002/011, and Defluviitaleacea-UCG-011, and testosterone levels. In conclusion, long-term ADT use in prostate cancer patients was associated with detrimental changes in gut microbiota, including an increase in genera related to testosterone synthesis and opportunistic bacteria. These changes may be related to disease progression and side effects of long-term ADT while further longitudinal studies are required to prove this relationship.

IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer.

Androgen deprivation therapy (ADT) forms the cornerstone of treatment in locally advanced and metastatic prostate cancer (PCa). Since the growth hormone-insulin-like growth factor (GH-IGF-1) axis has been implicated in prostate tumorigenesis, we aimed to evaluate the association between IGF-1 and its binding proteins on outcomes in men with metastatic PCa treated with ADT, with or without docetaxel (D). We analyzed serum samples for IGF-1 and its family proteins from baseline, 6 months post-randomization, and at the time of progression in men enrolled to receive ADT +/- D in the phase 3 CHAARTED trial. The key outcomes were time to the development of castrate-resistant prostate cancer and overall survival (OS). About 560 patients had samples available for analysis. At 6 months, significant increases in IGF-BP1 (mean Δ+27.4%, P = 0.033), IGF-BP3 (mean Δ+10.3%, P < 0.001), and IGF-BP4 (mean Δ+31.1%, P < 0.001) were seen in the ADT + D group, while the ADT group showed an increase in IGF-BP3 (mean Δ+5.5%, P = 0.015). A higher IGF-1:IGF-BP1 ratio at baseline and after 6 months was associated with improved OS in both the ADT (baseline: hazard ratio (HR) = 0.77, P = 0.026; 6 months: HR = 0.83, P = 0.036) and ADT + D groups (baseline: HR = 0.78, P = 0.04; 6 months: HR = 0.81, P = 0.018). Patients with a log10IGF-1:IGF-BP1 ratio >1.3 at baseline had improved OS when meta-analyzed with data from a prior cohort (HR = 0.71). A higher baseline and 6-month IGF-1:IGF-BP1 ratio was associated with better OS. Further exploration of the IGF-1 axis will be important to assess its role as a predictive biomarker and to target this axis in therapeutic trials.

Androgen deprivation therapy plus abiraterone or docetaxel as neoadjuvant therapy for very-high-risk prostate cancer: a pooled analysis of two phase II trials.

Objective: The study aimed to compare the efficacy and safety of androgen deprivation therapy (ADT) with abiraterone or docetaxel versus ADT alone as neoadjuvant therapy in patients with very-high-risk localized prostate cancer. Methods: This was a pooled analysis of two single-center, randomized, controlled, phase II clinical trials (ClinicalTrials.gov: NCT04356430 and NCT04869371) conducted from December 2018 to March 2021. Eligible participants were randomly assigned to the intervention (ADT plus abiraterone or docetaxel) and control (ADT alone) groups at a 2:1 ratio. Efficacy was evaluated by pathological complete response (pCR), minimal residual disease (MRD), and 3-year biochemical progression-free survival (bPFS). Safety was also analyzed. Results: The study included 42 participants in the ADT group, 47 in the ADT plus docetaxel group, and 48 in the ADT plus abiraterone group. A total of 132 (96.4%) participants had very-high-risk prostate cancer, and 108 (78.8%) had locally advanced disease. The ADT plus docetaxel group (28%) and ADT plus abiraterone group (31%) had higher rates of pCR or MRD (p = 0.001 and p < 0.001) compared with the ADT group (2%). The 3-year bPFS was 41.9% (95% CI: 26.6-57.2), 51.1% (95% CI: 36.8-65.4), and 61.2% (95% CI: 45.5-76.9), respectively. Significant difference was found among groups in terms of bPFS (p = 0.037). Conclusion: Compared with ADT alone, neoadjuvant therapy with ADT plus docetaxel or abiraterone could achieve better pathological outcomes (pCR or MRD) for very-high-risk localized prostate cancer. The ADT plus abiraterone group showed longer bPFS than ADT alone. The combination regimens were tolerable.

Androgen-deprivation therapy and risk of dementia in patients with prostate cancer: Clinical outcomes from real-world data.

5086 Background: Androgen deprivation therapy (ADT) is the cornerstone for the treatment advanced prostate cancer. However, there has been growing concerns regarding increased risk of dementia with ADT. Previous studies of dementia risk following ADT were controversial and inconclusive. Methods: Data was collected from an electronic health record database (TriNetX LLC., Cambridge, MA) which includes over 89 million patients from 56 healthcare systems in the United States. We identified males over the age 50 years who were diagnosed with any stage of prostate cancer between 2005 and 2022. Patients receiving ADT were 1:1 propensity score-matched with non-exposed controls for demographics and risk factors for dementia; diabetes mellitus, hypertension, hyperlipidemia, obesity, depression, cerebrovascular disease, tobacco use, alcohol dependence and benzodiazepine use. Patients with prior dementia, stroke, or TIA were excluded. Results: In a cohort of 627,025 men with prostate cancer, 73,933 patients (mean age of 70.8 years) received ADT and 57,005 patients (mean age of 70.4 years) did not. ADT exposure was associated with a diagnosis of dementia (Alzheimer’s disease, vascular dementia, or unspecified dementia); HR 1.6; 95% CI (1.49, 1.73). Subgroup analysis by dementia subtype is highlighted in (table). Compared to non-ADT group, exposure to ADT was associated with a statistically higher risk of dementia among whites (78.6% vs. 77.7%, P &lt;0.001), whereas there was no significant difference among African Americans. The risk of dementia with different ADT regimens is shown. Conclusions: This is the largest real-world study describing the association between ADT and the risk of dementia, including over 600 thousand prostate cancer patients. The risk of dementia was significantly higher in patients on ADT, with a 60% increased risk. The highest risk was witnessed with GnRH antagonists (degarelix), with a 92% increased risk. Interestingly, the increased risk of dementia in ADT groups was observed only among whites but not in African Americans. Possible causes of this discrepancy include socioeconomic disparities, bias that resulted in underdiagnosis, or biological differences. [Table: see text]

The Use of Androgen Deprivation Therapy for Prostate Cancer Lead to Similar Rate of Following Open Angle Glaucoma: A Population-Based Cohort Study.

This study aimed to survey the effect of androgen deprivation therapy (ADT) on the development of open angle glaucoma (OAG) in prostate cancer using the data from national health insurance research database (NHIRD) of Taiwan. A retrospective cohort study was conducted and patients were regarded as prostate cancer with ADT according to related diagnostic, procedure and medication codes. Each prostate subject with ADT was matched to one patient with prostate cancer, but without ADT, and two participants without both prostate cancer and ADT; 1791, 1791 and 3582 patients were recruited in each group. The primary outcome was set as the OAG development according to related diagnostic codes. Cox proportional hazard regression was used to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of ADT for the incidence of OAG. There were 145, 65 and 42 newly developed OAG cases in the control group, prostate cancer without ADT group and prostate cancer with ADT group. The prostate cancer with ADT group showed a significantly lower risk of OAG development compared to the control group (aHR: 0.689, 95% CI: 0.489-0.972, p = 0.0341), and the risk of OAG development in the prostate cancer without ADT group was similar compared to that in the control group (aHR: 0.825, 95% CI: 0.613-1.111, p = 0.2052). In addition, ages older than 50 years old would lead to higher incidence of OAG development, respectively. In conclusion, the use of ADT will lead to a similar or lower rate of OAG development.

Association of Androgen Deprivation Therapy with Osteoporotic Fracture in Patients with Prostate Cancer with Low Tumor Burden Using a Retrospective Population-Based Propensity-Score-Matched Cohort.

This study evaluated the effect of androgen deprivation therapy (ADT) on osteoporotic fractures (OF) and its prognostic effect on overall survival in patients with localized or regional prostate cancer (PC) using the Korean National Insurance Dataset. A total of 8883 pairs of 1:1 propensity-score-matched patients with localized or regional PC were retrospectively enrolled between 2007 and 2016. All patients underwent at least 1 year of follow-up to evaluate therapeutic outcomes. Multivariate analysis was performed to determine the prognostic effect of ADT on OF. During a mean follow-up of 47.7 months, 977 (3.43%) patients developed OF, and the incidences of hip, spine, and wrist fractures were significantly different between ADT and non-ADT groups (p < 0.05). The ADT group had a significantly higher incidence of OF (hazard ratio 2.055, 95% confidence interval 1.747-2.417) than the non-ADT group (p < 0.05), and the incidence of spine/hip/wrist OF was significantly higher in the ADT group regardless of the PC stage (p < 0.05). Multivariate analysis failed to show any significant difference in overall survival between the two groups (p > 0.05). ADT resulted in a significantly higher incidence of OF among patients with localized and regional PC, but the overall survival did not differ between ADT and non-ADT groups.

MP77-19 IS ANDROGEN DEPRIVATION THERAPY ASSOCIATED WITH CEREBRAL INFARCTION IN PATIENTS WITH PROSTATE CANCER? A KOREAN NATIONWIDE POPULATION-BASED PROPENSITY SCORE MATCHING STUDY

You have accessJournal of UrologyCME1 Apr 2023MP77-19 IS ANDROGEN DEPRIVATION THERAPY ASSOCIATED WITH CEREBRAL INFARCTION IN PATIENTS WITH PROSTATE CANCER? A KOREAN NATIONWIDE POPULATION-BASED PROPENSITY SCORE MATCHING STUDY Bum Sik Tae, Jung Wan Yoo, Hoon Choi, Jae Hyun Bae, and Jae Young Park Bum Sik TaeBum Sik Tae More articles by this author , Jung Wan YooJung Wan Yoo More articles by this author , Hoon ChoiHoon Choi More articles by this author , Jae Hyun BaeJae Hyun Bae More articles by this author , and Jae Young ParkJae Young Park More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003351.19AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Previous studies have suggested that androgen deprivation therapy (ADT) is associated with cerebral infarction. However, conflicting results have been reported by other researchers. The aim of the present study was to evaluate the association between ADT and cerebral infarction in patients with prostate cancer (PC) using big data. METHODS: Using information from the National Health Insurance Service database representative of the entire Korean adult PC population (n=206,735), data regarding ADT and cerebral infarction between 2009 and 2016 were analyzed. Adjusted hazard ratios for cerebral infarction associated with ADT were estimated using propensity score-matched Cox proportional hazards models and Kaplan-Meier survival analyses. RESULTS: The final cohort comprised 36,146 individuals with PC, including 24,069 men (66.6%) who underwent ADT. During the mean follow-up of 4.1 years, 2792 patients were newly diagnosed with cerebral infarction. In the unmatched cohort, there was a significant difference in the annual incidence of cerebral infarction between the ADT and non-ADT groups (22.8 versus [vs] 14.6 per 1000 person-years, respectively). However, there was no significant difference between the ADT and non-ADT groups in the matched cohort (14.9 vs 14.6 per 1000 person-years). The adjusted hazard ratio for cerebral infarction for PC patients who underwent ADT was 1.045 (95% CI 0.943–1.159; p=0.401) compared with those who did not undergo ADT. In addition, the cumulative duration of ADT was also not associated with an increased risk for cerebral infarction. However, older age, hypertension, diabetes, myocardial infarction, congestive heart failure, peripheral vascular disease, renal disease, dementia, and atrial fibrillation were revealed to be factors contributing to cerebral infarction. CONCLUSIONS: This nationwide population-based study revealed that ADT was not associated with cerebral infarction after adjusting for potential confounders. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1109 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bum Sik Tae More articles by this author Jung Wan Yoo More articles by this author Hoon Choi More articles by this author Jae Hyun Bae More articles by this author Jae Young Park More articles by this author Expand All Advertisement PDF downloadLoading ...

MP11-11 TAILORING THE OPTIMAL USE OF ANDROGEN-DEPRIVATION THERAPY CONCOMITANT TO POST-OPERATIVE RADIOTHERAPY AMONG MEN WITH PN1 PROSTATE CANCER. LONG-TERM RESULTS OF A LARGE, SINGLE INSTITUTION SERIES

MP11-11 TAILORING THE OPTIMAL USE OF ANDROGEN-DEPRIVATION THERAPY CONCOMITANT TO POST-OPERATIVE RADIOTHERAPY AMONG MEN WITH PN1 PROSTATE CANCER. LONG-TERM RESULTS OF A LARGE, SINGLE INSTITUTION SERIES

Intensity-modulated radiation therapy for intermediate-risk prostate cancer: does ADT still have an impact in the dose-escalated external beam radiation therapy era?

This study aimed to investigate the effect of androgen deprivation therapy (ADT) on the survival of intermediate-risk prostate cancer (IR-PCA) patients treated with dose-escalated external beam radiation therapy (DE-EBRT), and to determine the group that will benefit from ADT. We analysed 620 IR-PCA patients treated with DE-EBRT at two institutions. Variables were adjusted using the stabilised inverse probability of treatment weighting method (sIPTW) between radiation therapy (RT) and RT plus ADT groups. Biochemical relapse-free survival (bRFS) rate and overall survival (OS) rate were compared using Kaplan-Meier analysis and log-rank test. Cox proportional hazard analysis (CPH) was conducted to detect unfavorable risk factors. This study included 405 patients; with 217 and 188 patients in the RT and RT plus ADT groups, respectively. The prescribed radiation dose was 78Gy in 39 fractions. The median follow-up time was 82.0months. After sIPTW-adjustment, 214.3 and 189.7 patients were assigned to the RT and RT plus ADT groups, respectively. The 7-year bRFS and OS were 89.3% and 94.6% in RT group and 92.3% and 91.0% in RT plus ADT group, respectively. Before and after sIPTW adjustment, no statistically significant differences were found in these endpoints between treatment groups. Multivariate CPH for bRFS revealed Gleason score (GS) 4+3 as an unfavorable risk factor, and ADT improved biochemical control of them. ADT may not always be effective in all Japanese IR-PCA patients treated with DE-EBRT, but it can improve biochemical control in patients with GS 4+3.