Duration Of Androgen Deprivation Therapy Research Articles

Androgen Deprivation Therapy and Newly Developed Neovascular Age-Related Macular Degeneration Risk in Patients with Prostate Cancer.

Background/Objectives: to evaluate the association between androgen deprivation therapy (ADT) and newly developed neovascular age-related macular degeneration (AMD) in patients with prostate cancer. Methods: We identified 228,803 men from the nationwide claims database in the Republic of Korea diagnosed with prostate cancer between 1 August 2009 and 31 December 2018 and followed until April 2021. Cases were defined as those newly diagnosed with neovascular AMD during follow-up. Cases were matched with controls based on age, index date, and follow-up duration, at a case-to-control ratio of 1:4. Adjusted odds ratios (aORs) of incident neovascular AMD associated with ADT were estimated using conditional logistic regression. Results: The main analysis included 1700 cases and 6800 controls, with a median follow-up of 3.42 years. ADT was associated with a reduced risk of incident neovascular AMD in patients with prostate cancer (aOR = 0.840; 95% confidence interval [CI], 0.743-0.951; p = 0.0058) in the multivariable analysis. A cumulative ADT duration less than 1 year was associated with a reduced risk of neovascular AMD (aOR = 0.727; 95% CI, 0.610-0.866; p = 0.0004); however, no association was observed when the duration of ADT was between 1 and 2 years (aOR = 0.862; 95% CI, 0.693-1.074; p = 0.1854) or more than 2 years (aOR = 1.009; 95% CI, 0.830-1.226; p = 0.9304). Conclusions: In patients with prostate cancer, medical castration for less than a year is associated with a reduced risk of incident neovascular AMD. These results suggest that androgens are involved in the pathogenesis of neovascular AMD.

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.

Testosterone recovery after androgen deprivation therapy in localised prostate cancer: Long-term data from two randomised trials

Background and purposeTo determine the rate and time of testosterone (T) recovery in patients (pts) with localised prostate cancer treated with radiotherapy plus 0-, 6-, 18- or 36-month of androgen deprivation therapy (ADT). Materials and methodsIn 1230 pts with prostate cancer randomised into two phase III trials, serum T was measured at baseline, then regularly. T recovery rate was compared between normal vs. abnormal baseline T and with ADT duration with Chi-square test or Fisher's exact test. A multivariable logistic regression model to predict the probability of recovering normal T was performed. ResultsOverall, 87.4 % (167/191), 75.9 % (293/386), 54.8 % (181/330) and 43.2 % (80/185) of pts, recovered normal T on the 0-, 6-, 18- or 36-month schedule, respectively (p < 0.001). In patients recovering normal T, the median time to T recovery increased with ADT duration ranging from 0.31, 1.64, 3.06 to 5.0 years for the 0-, 6-, 18- or 36-month schedules, respectively (p < 0.001) and was significantly faster for those with a normal T at baseline (p < 0.001). On multivariable analysis, older age and longer ADT duration are associated with a lower T recovery. ConclusionsTestosterone recovery rate after ADT depends on several factors including hormonal duration, normal baseline T, age and medical comorbidities. A longer ADT duration is the most important variable affecting T recovery. The data from this report might be a valuable tool to help physicians and patients in evaluating risks and benefits of ADT.

Effects of Androgen Deprivation Therapy Duration on Health-Related Quality of Life, Physical Activity, Anxiety and Depression Levels in Patients with Intermediate- and High-Risk Prostate Cancer

Effects of Androgen Deprivation Therapy Duration on Health-Related Quality of Life, Physical Activity, Anxiety and Depression Levels in Patients with Intermediate- and High-Risk Prostate Cancer

Initial management approach for localized/locally advanced disease is critical to guide metastatic castration-resistant prostate cancer care.

Currently, several therapies are available for metastatic castration-resistant prostate cancer (mCRPC) but no specific clinical factors to personalize treatment. We first sought the prognostic value of duration on androgen-deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) in patients receiving androgen-receptor-signaling inhibitors (ARSI) for mCRPC. A multicenter cohort of mCRPC patients who started ARSI between July 2011 and October 2021 was identified. Based on their initial disease burden and duration on ADT for HSPC, primary progressive (PP) men were classified into four groups: low/intermediate-risk localized disease (LOC) and high-risk localized/locally advanced disease (LAD) and short-term (ST) < 24 vs. long-term (LT) ADT ≥ 24 months, whereas de novo (DN) mHSPC were subdivided into short-time vs. long-time to CRPC. We included 919 mCRPC patients with a median age of 77 years [interquartile range (IQR) = 71-82)]. Median ADT duration in HSPC was 24 months (IQR = 14-40). Median follow-up was 91 months (IQR = 62-138), median OS and PFS from ARSI start were 20 (IQR 10-32) and 10 months (IQR = 5-19), respectively. In PP developing metastatic disease (n = 655, 71.3%), LOC and LAD with ST ADT had a greater than almost double-risk of death compared to LT ADT (LOC/ST: hazard ratio [HR] = 2.01; 95% CI 1.54-2.64; LAD/ST: HR = 1.73; 95% CI 1.34-2.24; p < 0.001). In the multivariate analysis including age, prognostic cohort, Gleason, ECOG, radical radiotherapy and prostatectomy, groups with ST ADT were associated with worse OS compared to LT ADT (LOC/ST: HR = 1.84; 95% CI 1.38-2.45; p < 0.001; LAD/ST: HR = 1.59; 95% CI 1.21-2.10; p < 0.001), along with ECOG > 2 (HR = 1.55; 95% CI 1.06-2.26; p = 0.03). There were also similar results of PFS. Moreover, long-time to CRPC in patients with history of DN mHSPC (n = 264, 28.7%) resulted in a better OS/PFS (HR = 0.76, 95% CI 0.56-1.02, p = 0.064 and HR = 0.74, 95% CI 0.55-0.99, p = 0.042, respectively). Our study showed that duration on ADT for mHSPC was significantly associated with survival in mCRPC undergoing ARSI. These findings suggest a possible connection between initial management of prostate tumour and a better prognostication in mCRPC. Prospective trials are warranted.

(177) Androgen Deprivation Therapy Does Not Increase Rates for Reintervention, Complication, or Infection in Penile Implant or Artificial Urinary Sphincter Surgery

Abstract Introduction Prostate cancer treatment carries significant quality of life implications, namely erectile dysfunction and stress urinary incontinence. Treatment options include genitourinary implants such as inflatable penile prosthesis (IPP) or artificial urinary sphincter (AUS). Given the association with androgens and penile and urethral health, there may be concern patients on androgen deprivation therapy (ADT) could have worse outcomes following IPP and AUS. Objective To evaluate whether patients on ADT undergoing IPP and AUS surgery are at increased risk for reintervention, complication, and infection. Methods We queried TriNetX, a collaborative research enterprise, for all adult male patients undergoing AUS or IPP. Cohorts were defined by those taking ADT 3 months before or anytime after surgery and those not taking ADT. ADT medications included: leuprolide, bicalutamide, flutamide, nilutamide, apalutamde, and darolide. We performed sub-analysis for leuprolide and bicalutamide, the two most prescribed ADT medications. Cohorts and outcomes were defined using Current Procedural Terminology (CPT) and International Classification of Diseases (ICD-10) codes. We used the impact of age, prostate cancer, history of prostatectomy and history of radiation to generate propensity score matching (PSM). Our primary outcome was need for reintervention (revision, removal, or replacement surgery based on CPT codes). Secondary outcomes included infection rate and complication rate based on ICD-10 codes. Analytics were performed via TriNetX on demographic data which calculated Risk Ratios and were run July 2023. Results There were 12,143 patients who received an IPP and 5487 who received an AUS (Table 1), with. 401 and 635 patients on ADT, respectively. Patients on ADT had similar rates of reintervention (9.4% vs 12.9%, RR = 0.72, p = 0.11), complication (17.7% vs 22.8%, RR =0.78, p=0.08), and infection (4.1% vs 4.8%, RR =0.84, p=0.60) for IPP. For bicalutamide, patients had lower complication rates (11.3% vs 18.2%, RR = 0.62, p=0.04) and similar reintervention rates (5.2% vs 9.9%, RR = 0.52, p=0.07). There were less than 10 instances of infection and thus TriNetX rounded these numbers to 10 (denoted by *) as part of a patient safety mechanism. Rates were similar for patients on leuprolide (reintervention: 9.8% vs 8.9%, RR =1.1, p = 0.69, complication: 17.5% vs 17.8%, RR = 0.98, p=0.92, infection: 4.0% vs 4.9%, RR = 0.81, p=0.57). Patients receiving an AUS showed similar rates for reintervention (20.8% vs 24.0% RR =0.87, p=0.17), complications (26.1% vs 25.6%, RR=1.0, p=0.85), and infections (2.3% vs 3.7%, RR=0.61, p=0.13) regardless of ADT. This held true for subanalyses for bicalutamide (reintervention: 22.7% vs 22.3%, RR =1.0, p = 0.92, complication: 27.7% vs 24.6%, RR = 1.1, p=0.43, infection: 3.8%* vs 3.8%*, RR = 1, p=1)., and leuprolide (reintervention: 19.8% vs 23.3%, RR =0.85, p = 0.18, complication: 25.3% vs 28.7%, RR = 0.8, p=0.21, infection: 1.9%* vs 3.2%, RR = 0.59, p=0.17). Conclusions Patients with IPP or AUS seemingly do no worse on ADT and in some comparisons even seemed to fare better. Further evaluation into the duration of ADT may provide clinical context, but based on these results, ADT should not limit implant surgery. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Boston Scientific, Coloplast.

Weight variation during androgen deprivation therapy in patients with localized prostate cancer: Data from two prospective randomized trials.

296 Background: In prostate cancer (PCa) treated with androgen deprivation therapy (ADT) and radiotherapy (RT), limited prospective data exist regarding weight variation during ADT. Using our prospective data from two phase III trials we compare the magnitude of weight variation during different duration of ADT. Methods: 400 patients (pts) with intermediate risk PCa received 6 months of ADT (Bicalutamide 1 month (m) and Goserelin 10,8 mg x 2), and 630 pts with high-risk PCa were treated with 18 or 36m of ADT (Bicalutamide 1m and Goserelin 10,8 mg x 6 or 12). Pts’ weights were measured at baseline then at each Goserelin dose. 463/1030 pts were excluded from the analysis: 90 no or incomplete ADT, 127 no initial weight and 246 no weight at the end of ADT. Regular patient weighing was available in 567/1030 pts (55%) from whom 250, 191 and 124 received, respectively, 6, 18 or 36m of ADT. Pt’s characteristics and weights were compared with Kruskal-Wallis and Chi squared test between groups of ADT. Multivariable logistic regression was performed to assess predictors of weight gain over 2 kg. Variables included were duration of ADT, age ≥65 vs. &lt; 65 and baseline comorbidities (cardiovascular disease, diabetes, chronic obstructive pulmonary disease, hypertension). Results: Comparing weights between the beginning and the end of ADT, 375/567 (66.1%) pts gained and 192/567 (33.9%) lost weight. The mean ± SD weight gain at the end of ADT was significantly higher in pts receiving 18m of ADT (1.98 ± 4.05) or 36m (2.38 ± 5.15) compared to pts receiving only 6m (0.98 ± 3.10, p=0.003). As ADT duration increased (6, 18 or 36m), weight gain over 2 kg (34.1% vs. 48.2% vs. 53.2%, p&lt;0.001) and over 4 kg (12.7% vs. 26.2% vs. 36.3%, p&lt;0.001) significantly increased. In multivariable logistic regression, predictors of weight gain over 2 kg were 18m ADT [OR=1.85 (1.25-2.74), p=0.002] and 36m ADT [OR=2.23 (1.43-3.48), p&lt;0.001] compared to 6m ADT and non-diabetic pts (OR=2.13 (1.28-3.54), p=0.003). Age was not a factor. In the 375 pts who gained weight, the rate of patients that gained 0.1 to 2 kg, 2.1 to 4 kg and more than 4 kg were respectively (47.2%, 33.1% and 19.6%) in the 163 receiving 6m ADT, (30.3%, 32.6% and 37.1%) in 132 pts receiving 18m ADT, and (17.6%, 26.3% and 56.4%) in the 80 pts receiving 36m ADT. In the 192 pts who lost weight, the rate of patients that lost 0.1 to 2 kg, 2.1 to 4 kg and more than 4 kg were respectively (62.9%, 21.3% and 15.6%) in 89 receiving 6m ADT, (50.8%, 27.1% and 22.1%) in 59 pts receiving 18m ADT and (59.1%, 15.9% and 25%) in 44 pts receiving 36m ADT. Conclusions: ADT is not associated with weight gain in all pts. Based on our prospective data, one third of pts lose weight at the end of ADT. However, weight gain above 2 kg or 4 kg increases with ADT duration and non-diabetics pts, regardless of age. Weight monitoring in pts receiving ADT should be done regularly and pts counseled accordingly.

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.

Unraveling the safety of adjuvant radiotherapy in prostate cancer: impact of older age and hypofractionated regimens on acute and late toxicity - a multicenter comprehensive analysis.

The objective of this study was to assess the impact of age and other patient and treatment characteristics on toxicity in prostate cancer patients receiving adjuvant radiotherapy (RT). This observational study (ICAROS-1) evaluated both acute (RTOG) and late (RTOG/EORTC) toxicity. Patient- (age; Charlson's comorbidity index) and treatment-related characteristics (nodal irradiation; previous TURP; use, type, and duration of ADT, RT fractionation and technique, image-guidance systems, EQD2 delivered to the prostate bed and pelvic nodes) were recorded and analyzed. A total of 381 patients were enrolled. The median EQD2 to the prostate bed (α/β=1.5) was 71.4 Gy. The majority of patients (75.4%) were treated with intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Acute G3 gastrointestinal (GI) and genitourinary (GU) toxicity rates were 0.5% and 1.3%, respectively. No patients experienced >G3 acute toxicity. The multivariable analysis of acute toxicity (binomial logistic regression) showed a statistically significant association between older age (> 65) and decreased odds of G≥2 GI acute toxicity (OR: 0.569; 95%CI: 0.329-0.973; p: 0.040) and decreased odds of G≥2 GU acute toxicity (OR: 0.956; 95%CI: 0.918-0.996; p: 0.031). The 5-year late toxicity-free survival rates for G≥3 GI and GU toxicity were 98.1% and 94.5%, respectively. The only significant correlation found (Cox's regression model) was a reduced risk of late GI toxicity in patients undergoing hypofractionation (HR: 0.38; 95% CI: 0.18-0.78; p: 0.008). The unexpected results of this analysis could be explained by a "response shift bias" concerning the protective effect of older age and by treatment in later periods (using IMRT/VMAT) concerning the favorable effect of hypofractionation. However, overall, the study suggests that age should not be a reason to avoid adjuvant RT and that the latter is well-tolerated even with moderately hypofractionated regimens.

Prospective study of HDR brachytherapy (BT), external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT): 10-years experience of an MRI-guided approach

ObjectivesTo evaluate the predictive factors for biochemical failure and distant metastases in a prospective cohort of patients with localized prostate cancer treated with the combination of HDR BT and EBRT. Methods and materialsPatients with intermediate (IR) or high-risk (HR) prostate adenocarcinoma received a single fraction of HDR of 15 Gy combined with RT of 37.5 Gy in 15 fractions. ADT duration was used depending on risk-group. Descriptive analyses were performed. Univariate and multivariate Hazard Ratios were obtained. Finally, the Kaplan-Meier model was used to describe the survival of the events of interest. Results309 patients were treated prospectively (199 were IR and 110 HR). Median age was 72 years; 58.3 % were MRI stage ≤ T2c, 34.1 % T3a and 7.6 % T3b; ISUP-grade 1–3 in 78.9 % and ISUP 4–5 in 21.1 %. 71.8 % of patients had ≤ 50 % positive-cores in biopsy and 28.2 % had > 50 %. Median pre-treatment PSA was 9.9 ng/mL. After a median follow-up of 88 months, 41 patients presented biochemical failure and 18 developed distant metastases. Multivariate cox-regression analyses found that MR-T3b Stage (HR 3.88, p = 0.001) and ADT use (HR 3.99, p = 0.03) were the only predictive factors for biochemical failure and the number of positive cores (>50 %) the only independent predictive factor of distant metastases (HR 4.36, p = 0.002). ConclusionsPatients with mpMRI evidence of invasion of the SV and involvement of more than 50% of the cores in the prostate biopsy are patients with a higher risk of presenting a biochemical recurrence or developing metastasis due to their prostate cancer, respectively.

Mortality Risk for Docetaxel-Treated, High-Grade Prostate Cancer With Low PSA Levels

Patients with high-grade prostate cancer with low levels of prostate-specific antigen (PSA; <4 ng/mL) are at high risk of mortality, necessitating an improved treatment paradigm. To assess for these patients whether adding docetaxel to standard of care (SOC) treatment is associated with decreased prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM). PubMed search from 2000 to 2022. Five prospective randomized clinical trials (RCTs) performed in the US, France, and the United Kingdom evaluating SOC treatment with radiotherapy and androgen deprivation therapy (ADT) or with radical prostatectomy vs SOC plus docetaxel. Individual data were included from patients with nonmetastatic prostate cancer, a PSA level of less than 4 ng/mL, and a Gleason score of 8 to 10. Patients initiated treatment between February 21, 2006, and December 31, 2015 (median follow-up, 7.1 [IQR, 5.4-9.9] years). Data were analyzed on December 16, 2022. Hazard ratio (HR) of ACM and subdistribution HR (sHR) of PCSM adjusted for performance status (1 vs 0 or good health), Gleason score (9 or 10 vs 8), tumor category (T3-T4 vs T1-T2 or TX), and duration of ADT (2 years vs 4-6 months). From a cohort of 2184 patients, 145 patients (6.6%) in 4 RCTs were eligible (median age, 63 [IQR, 46-67] years). Thirty-one patients died, and of these deaths, 22 were due to prostate cancer. Performance status was 0 for 139 patients (95.9%) and 1 for 6 patients (4.1%). A reduced but nonsignificant risk of ACM (HR, 0.51 [95% CI, 0.24-1.09]) and PCSM (sHR, 0.42 [95% CI, 0.17-1.02]) was associated with patients randomized to SOC plus docetaxel compared with SOC. The risk reduction in ACM (HR, 0.46 [95% CI, 0.21-1.02]) was more pronounced among patients with a performance status of 0 and was significant for PCSM (sHR, 0.30 [95% CI, 0.11-0.86]). Adding docetaxel to SOC treatment for patients who are in otherwise good health with a PSA level of less than 4 ng/mL and a Gleason score of 8 to 10 was associated with a significant reduction in PCSM and therefore has the potential to improve prognosis.

Mental health outcomes in a population-based cohort of patients with prostate cancer.

Few studies have evaluated mental health disorders comprehensively among patients with prostate cancer on long-term follow-up. The primary aim of our study was to assess the incidence of mental health disorders among patients with prostate cancer compared with a general population cohort. A secondary aim was to investigate potential risk factors for mental health disorders among patients with prostate cancer. Cohorts of 18 134 patients with prostate adenocarcinomas diagnosed between 2004 and 2017 and 73470 men without cancer matched on age, birth state, and follow-up time were identified. Mental health diagnoses were identified from electronic health records and statewide health-care facilities data. Cox proportional hazard models were used to estimate hazard ratios. All statistical tests were 2-sided. The hazard ratios for mood disorders, including depression, among prostate cancer survivors increased for all follow-up periods compared with the general population. The hazard ratios for any mental illness increased with Hispanic, Black, or multiple races; people who were underweight or obese; those with advanced prostate cancer; and those undergoing their first course cancer treatment. We also observed statistically significantly increased hazard ratios for mental health disorders among patients with lower socioeconomic status (P < .0001) and increasing duration of androgen-deprivation therapy (P = .0348). Prostate cancer survivors had a 61% increased hazard ratio for death with a depression diagnosis. Prostate cancer diagnosis was associated with a higher risk of mental health disorders compared with the general population, which was observed as long as 10-16 years after cancer diagnosis. Providing long-term mental health support may be beneficial to increasing life expectancy for patients with prostate cancer.

ADT Use and Nodal Irradiation in Men Receiving Post-Prostatectomy Salvage Radiotherapy within a Statewide Radiation Oncology Quality Consortium.

For men with biochemical recurrence after radical prostatectomy, salvage radiotherapy (SRT) is a standard of care. Outcomes are improved when SRT is delivered at lower PSA levels, and there has been increased emphasis on more timely treatment. With early SRT, however, there remains uncertainty as to the optimal use and duration of androgen deprivation therapy (ADT) and pelvic lymph node radiation (PLNRT). Moreover, PET imaging and genomic classifiers have emerged as tools to guide treatment decisions, but their uptake in routine practice is unknown. To address these questions, we analyzed a contemporary cohort treated with SRT within the Michigan Radiation Oncology Quality Consortium (MROQC). We hypothesized that ADT and PLNRT practices would reflect recent trial results in this setting. Eligible patients receiving SRT at an MROQC center were enrolled from 06/09/20 to 11/04/22. Data was prospectively collected via patient-, physician-, and physicist-completed forms. Patients were matched to the Michigan Urological Surgery Improvement Collaborative (MUSIC) database for additional treatment- and patient-related data. Univariable (UVA) and multivariable analyses (MVA) were performed to test associations between patient/tumor factors and ADT or PLNRT use. A total of 191 patients across 26 centers were enrolled in the MROQC database. Of these, 116 were matched to the MUSIC database. Median time from RP to SRT was 17 months (IQR 8 - 33 months). The median post-RP PSA prior to SRT was 0.25 (IQR 0.16 - 0.60). Early SRT was defined as pre-SRT PSA ≤0.5, and 27% (n = 31/116) had a pre-SRT PSA >0.5. Twenty-eight were pT3b/T4, 97% were pN0/NX, and 51% had positive surgical margins. Fractionation was conventional (>28 fractions) in 58% and moderate hypofractionation (20-28 fractions) in 38%. Table 1 describes the patients receiving ADT and/or PLNRT. Median ADT duration was 6 mo (IQR 6 - 7 mo). MVA revealed pre-SRT PSA >0.5 (OR 5.05 [1.89 - 15.33]) and pT3b/T4 disease (OR 4.23 [1.40 - 14.56]) were significantly associated with ADT use (p <0.05), but not grade group (GG) or margin status. PLNRT was significantly associated with pre-SRT PSA >0.5 (OR 3.04 [1.21 - 8.42], p <0.05) but not pT stage, margin status, or GG. PET imaging was performed in 37% of men (52% negative, 21% prostate bed alone uptake, and 26% lymph node positivity) and genomic classifiers were performed in 24%. Nearly 75% of biochemically recurrent prostate cancer patients within MROQC received early SRT, and about half received ADT. A pre-SRT PSA >0.5 was strongly associated with ADT and PLNRT. With prostate bed SRT alone, very few received ADT. Given the considerable heterogeneity in treatment, additional studies may help identify patients who most benefit from ADT + PLNRT, and who may be spared potential added toxicity.

Real-World Treatment Patterns Among French Patients With Metastatic Castration-Resistant Prostate Cancer Under Abiraterone or Enzalutamide.

Using large French retrospective study cohort of chemotherapy-naïve metastatic castration-resistant prostate cancer patients (mCRPC; n=10,308) comparing survival between patients who initiated abiraterone (ABI; 64%) and those initiating enzalutamide (ENZ; 36%), the present objective was to describe treatment patterns in the 2 years following initiation. Using the national health data system (SNDS) from 2014 to 2018, we first explored the number of treatment lines, and secondly, patterns of patient management using state sequence analysis; cluster analyses were performed on the 0 to 12 month and 13 to 24 month periods. Age, Charlson score, and duration of androgen deprivation therapy (ADT) were obtained for each cluster in the first year of follow-up. Patients with only 1 treatment line accounted for 52%. In the 0 to 12 month sequence analysis, the main clusters among ABI/ENZ new users involved patients who continued the initial treatment (54% of 65% respectively) and discontinued active treatment (14.5% for both). Less than 2 years exposure to ADT prior to ABI/ENZ initiation was frequently observed for noncontrolled mCRPC, as shown in the death and switch from ABI/ENZ to docetaxel clusters. The clusters for a switch ABI/ENZ to ENZ/ABI involved 6% to 11% of the patients. Our study suggested fairly similar patterns between ABI and ENZ initiation. The cluster of patients with active treatment discontinuation needs to be further investigated, as well as factors influencing therapeutic choice. Better understanding for the use of second-generation hormone therapy in mCRPC in real life, could improve its implementation by clinicians in the early stages of prostate cancer.

A Systematic Review and Network Meta-Analysis Assessing the Impact of Adding First Generation Non-Steroidal Anti-Androgens (NSAA) to LHRH Agonists (LHRHa) in Men Receiving Radiotherapy for Localized Prostate Cancer.

Randomized clinical trials consistently demonstrate that the addition of androgen deprivation therapy (ADT) to prostate radiation therapy improves overall survival (OS). However, there is substantial heterogeneity regarding the type of ADT: LHRHa alone, first generation NSAA alone (e.g., bicalutamide) or combination androgen blockade (CAB) with NSAA and LHRHa. There are no published randomized trials in localized disease that specifically compare the efficacy of NSAA to LHRHa, nor the utility of CAB over monotherapy ADT. We herein performed a systematic review and network meta-analysis to assess the impact of NSAA in relation to LHRHa in men receiving radiotherapy for localized prostate cancer. We performed a systematic literature search in PubMed to identify clinical trials of patients with localized prostate cancer for which ADT duration was the primary randomization variable. Both definitive and salvage radiation trials were included. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from data extracted from published survival curves. A network meta-analysis was performed to compare OS by ADT regimens. We defined NSAA toxicity as early discontinuation of any ADT agent due to side effects given the inconsistent reporting of specific related toxicity. A meta-regression was performed to assess association with NSAA toxicity, adjusted for study year, patient age, T stage, Gleason score and total ADT duration. NSAA duration was assessed as a continuous variable. Of the 11 trials (8,169 patients) with OS data, the median duration of any ADT was 3 months (range 0-36 months) and the median duration of NSAA specifically was 3.5 months (range 0-24 months). There was no significant difference in OS between those treated with LHRHa (n = 369) vs. CAB (n = 4,792; HR 1.10, 95% CI 0.78-1.55). Among those receiving CAB, increased NSAA duration did not improve OS (versus 0 months; 1-6 months HR 1.41, 95% CI 0.94-2.13; 7-12 months HR 1.43, 95% CI 0.87-2.34) when controlling for total ADT duration. Of the 19 trials (15,067 patients) with toxicity data, patients on NSAA (n = 503) appeared more likely to discontinue treatment early compared to those receiving LHRHa (n = 902), though this was not statistically significant (odds ratio [OR] 4.20, 95% CI 0.16-109.19). A longer duration of NSAA did not adversely affect ADT compliance. Patients were more likely to discontinue ADT prematurely, regardless of type, if the planned duration was longer (OR 1.08, 95% CI 1.07-1.09). We did not detect an overall survival benefit to adding NSAA to LHRHa, and NSAA appeared less well tolerated than LHRHa in men receiving radiation therapy for localized prostate cancer. These data suggest that providers should consider LHRHa without the addition of a NSAA as optimal when clinically appropriate.

Multi-Institutional Analysis of Metastasis Directed Therapy with or without Androgen Deprivation Therapy in Oligometastatic Castration Sensitive Prostate Cancer.

Several prospective trials in oligometastatic castration sensitive prostate cancer (omCSPC) have shown metastasis-directed therapy (MDT) can delay time to progression and initiation of androgen deprivation therapy (ADT) compared to observation. However, the optimal integration of ADT with MDT remains unclear. Here we report a multi-national, multi-institutional retrospective cohort of omCSPC treated with MDT to characterize the long-term outcomes of patients treated with MDT alone or in combination with ADT. Patients with a controlled primary site and omCSPC (defined as ≤ 5 lesions on conventional imaging) treated with MDT with or without concurrent ADT and with at least 36 months follow-up were retrospectively screened across 13 institutions. The primary endpoints included biochemical progression free survival (bPFS) and radiographic progression free survival (rPFS) calculated using Kaplan-Meier method and stratified by treatment group (MDT alone vs MDT + ADT). Multivariable Cox regression was performed adjusted for variables found to be prognostic on univariate analysis. Among 414 patients screened, a total of 263 patients treated between 2003 and 2018 met inclusion criteria and included. Of these, 105 received MDT alone and 158 received MDT+ADT, with median follow-up of 49.5 and 54.5 months, respectively. The majority were metachronous (90%) and had bone lesions (60%). Median ADT duration was 21.3 months (IQR 12.0- 31.9). Patients who received ADT vs. no ADT had poorer prognostic features including 23% vs. 1% synchronous (p<0.001), and 55% vs 40% Gleason 8-10 (p = 0.012). ADT use was associated with a better 5-year bPFS 24% vs 11% (p<0.0001) and rPFS 41% vs 29% (p<0.001). On multivariable Cox regression adjusting for post-MDT PSA nadir and salvage therapy, ADT use maintained significance for both bPFS (HR 0.51 (0.36, 0.71), p<0.001) and rPFS (HR 0.67, 95% CI 0.46-0.96, p = 0.03). Long-term outcomes with MDT alone suggest a small proportion of patients experience sustained disease control. The addition of ADT appears to improve rPFS, however prospective studies are needed in order to allow for personalization of care in patients with omCSPC.

Impact of Prior Radiation Therapy on Bone Mineral Density Change Over Time: Secondary Analysis of the Control Arm of a Phase III Randomized Trial

Retrospective studies have demonstrated that pelvic radiation therapy (RT) can lead to decreased bone mineral density (BMD) and increased risk of fracture. This is more relevant for men with prostate cancer (PCa) who often receive androgen deprivation therapy (ADT) in conjunction with RT. We performed a post-hoc secondary analysis of publicly available data of the control arm of a phase III randomized controlled study (NCT00089674) to determine if history of prior pelvic RT affects change in BMD over time in non-metastatic PCa patients treated with ADT. In this study, PCa patients with age ≥70 years or <70 years with low BMD (T-score <-1) or history of osteoporotic fracture, on ADT for at least 12 months were randomized to receive densoumab vs. placebo every 6 months for 3 years. Additionally, all patients received daily vitamin D and calcium supplementation. Randomization was stratified by duration of prior ADT (≤6 months vs >6 months) and age (<70 vs ≥70 years). BMD was measured at baseline, and at months 1, 3, 6, 12, 24, and 36 with blind reading by central reviewer. To model the effect of prior pelvic RT on dynamic change in BMD in the hip, lumbar spine, and femoral neck, we applied separate multivariate linear mixed effect models for each site. Age, ECOG performance score, history and number of prior fractures, smoking history, and years from initial cancer diagnosis were included as fixed covariates while patients were included as random intercepts. Among 734 patients who were randomized to the control arm, 563 participants with baseline and at least one post baseline assessment of BMD were eligible for this analysis. Overall, 34.4% (n = 194) received prior RT. We did not find any significant association of dynamic change in BMD with receipt of prior pelvic RT for left femoral neck (p = 0.7), total hip (p = 0.8), and lumbar spine (p = 0.5), respectively. At 36 months, there was no significant association of prior RT with percent change in BMD in femoral neck (odds ratio [OR]: 0.85; 95% confidence interval [CI]: 0.30-2.41), total hip (OR: 0.96; 95% CI: 0.43-2.15), and lumbar spine (OR: 2.01; 95% CI: 0.63-6.45). However, note should be made of the opposite direction of association of prior RT with percent BMD change at 36 months for femoral neck and hip versus lumbar spine. In this exploratory analysis of the control arm of a phase III randomized trial, we did not find sufficient evidence of an association between prior pelvic RT and dynamic changes in BMD in femoral neck, hip, and lumbar spine over time in men with non-metastatic PCa and low BMD at baseline. This analysis should be interpreted cautiously considering its post-hoc nature with likely inadequate power, the possibility of selection bias, lack of information on receipt of prior ADT, and missing data in longitudinal assessments.

Disease and Toxicity Outcomes after Salvage Radiotherapy (SRT) for Biochemically Recurrent Prostate Cancer (PC) for Patients Enrolled in a Phase II, Open Label Trial Investigating Neoadjuvant Chemohormonal Therapy Followed by Radical Prostatectomy (RP)

Men with metastatic hormone sensitive prostate cancer have improved progression free and overall survival (PFS/OS) when treated with docetaxel and androgen deprivation therapy (ADT). Our institution conducted a phase II trial (UW17009) investigating the addition of three cycles of neoadjuvant docetaxel and ADT to RP in men with high-risk prostate cancer. Here we report toxicity and freedom from biochemical recurrence (FFBCR) for patients treated with SRT following participation in this trial. Between January 17, 2018 and August 10, 2021, 28 patients enrolled on UW17009. Patients who had a recurrence and received SRT were identified. Toxicity was assessed using modified LENT (Late Effects of Normal Tissues)/RTOG (Radiation Therapy Oncology Group) criteria, and time to recurrence following SRT was determined for each patient. Additionally, the months of ADT received by each patient was recorded. FFBCR was then determined for this cohort using the method of Kaplan and Meier. Of 28 patients enrolled on UW17009, 20 (71%) had BCR after RP. Of these, 19 received SRT, representing 68% of the patients enrolled on the trial. The rates of acute grade 1 and grade 2 GU toxicity with SRT were 37% (7) and 53% (10), respectively. The rates of acute grade 1 and grade 2 GI toxicity with SRT were 32% (6) and 37% (7), respectively. On patient experienced a grade 4 genitourinary toxicity during SRT. There were no acute grade 3 or grade 5 toxicities. The rates of late grade 1 and grade 2 GU toxicity were 16% (3) and 11% (2), respectively. The rates of late grade 1 and grade 2 GI toxicity were 11% (2) and 5% (1), respectively. There was 1 (5%) late grade 3 GU toxicity. There were no late grade 3-5 GI toxicities, or late grade 4-5 GU toxicities. The average duration of ADT after prostatectomy was 15 months (range: 0-37 months). According to the method of Kaplan and Meier, mean FFBCR after SRT was 34.0 months at a median of 37.8 months. Median FFBCR had not yet been reached. At the time of analysis, 13 patients remained free from biochemical recurrence after SRT. Rates of biochemical recurrence and SRT following neoadjuvant docetaxel and ADT and then RP were consistent with historical data, as was the rate of successful SRT. Toxicities were also consistent with historical data, though there was notably one acute grade 4 GU toxicity.

Androgen Deprivation Therapy Use among Intermediate Risk Prostate Cancer Patients Undergoing Radiation Therapy across a Statewide Radiation Oncology Quality Consortium

For men with intermediate (INT) risk prostate cancer, the addition of androgen deprivation therapy (ADT) reduces risk of PSA failure, distant metastasis, and cancer-related mortality. Moreover, the relative reduction in cancer-related adverse outcomes with ADT use appears consistent across all INT risk subgroups. The absolute benefit of ADT, however, varies by baseline risk. In contemporary practice, it is unknown which clinical factors are most strongly associated with intended ADT use. Therefore, we sought to identify such factors within the diverse practices of the Michigan Radiation Oncology Quality Consortium (MROQC). Patients with localized prostate cancer undergoing definitive radiation therapy were enrolled from 6/9/20 to 11/4/22 (n = 599). Standardized patient, physician, and physicist forms were used to collect baseline and follow-up information. Intended ADT use, defined by the treating physician, was prospectively collected and is the primary outcome of this analysis. Univariable (UVA) and multivariable analyses (MVA) associations with patient (age, race, comorbidities), tumor (T stage, Gleason, percent cores positive, and PSA), and practice-related (academic vs private) factors were performed. In addition, advanced modality testing (PET, MRI, and genomic classifiers) was available as of March 2021, and subgroup analysis were performed where appropriate. A total 351 patients across 26 centers were enrolled with INT risk disease. ADT use was intended for 46% of men (n = 162/351) which differed by men with NCCN favorable INT (21%, n = 22/105) vs unfavorable INT risk disease (57%, n = 140/246), p<0.001. Sixty two percent (n = 100/162) had an intended ADT duration of 4-6 months and 21% (n = 34/162) had ≥12 months. Older age was associated with ADT use (70 vs 67, p < 0.01); there were no significant differences by race or comorbidities number. MVA showed Gleason 4+3 (OR 4.61 [2.91 - 7.42]) and > = 50% positive cores (2.56 [1.52 - 4.37]) were significantly associated with ADT use. No significant differences were noted based on practice setting. Pelvic MRI was obtained for 71% of men (n = 197/279), genomic classifiers in 47% (n = 130/279), and PET in 2% (n = 6/282). In the subset with MRI (n = 197), adverse features (ECE, SVI, or equivocal LNs) were associated with intended ADT use (OR 3.0 [1.4 - 7.1]) after adjustment for NCCN favorable/unfavorable INT risk classification. Within a state-wide consortium, intended ADT use for intermediate prostate cancer is most strongly associated with Gleason score, ≥50% positive cores, NCCN unfavorable intermediate risk classification, and adverse features on MRI. Nearly half of men had genomic classifier testing underscoring the importance ongoing trials such as NRG/GU 010.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.