Androgen Deprivation Therapy Research Articles

Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023.

Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or docetaxel (DOC). To understand current treatment approaches in clinical practice, we examined combined therapy for mHSPC in US real-world practice. This retrospective study used administrative claims in the Komodo Research Dataset (January 2016-September 2023). Individuals with mHSPC were identified on the basis of their earliest claim for metastasis on/after prostate cancer diagnosis date without evidence of castration resistance. Index date was the earliest ADT claim after mHSPC. Combination therapy included the addition of ARPI, DOC, or both to ADT within 4 months of index date. Multinomial regression was used to examine factors associated with combination therapy. Study population consisted of 10,717 individuals, with a median age of 65 years and a majority of de novo mHSPC cases at diagnosis (62%). Overall, 28% received combination therapy with ARPI (18% abiraterone; 10% apalutamide, darolutamide, or enzalutamide), 9% with DOC, and 2.5% with ARPI plus DOC. From 2017 to 2023, combined hormonal therapy with ARPI increased from 13% to 47% and with ARPI plus DOC from 0.8% to 15%, whereas use of ADT plus DOC declined from 12% to 3% and ADT alone from 74% to 36%. Key factors associated with combination therapy were younger age, fewer chronic comorbidities, de novo mHSPC, and bone metastases. Although one third of men received ADT alone in 2023, the use of combination hormonal therapy with ARPI and/or DOC increased between 2017 and 2023, highlighting uptake of guideline-recommended treatment, driven by available clinical evidence, disease burden, and tolerability.

Longitudinal assessment of bone mineral density in prostate cancer patients: comparing metastatic and non-metastatic regions.

Prostate cancer patients receiving androgen deprivation therapy (ADT) have increased risks of decreased bone mineral density (BMD). However, there are no established guidelines for assessing BMD in patients with bone metastases. The aim of this study was to assess the effects of ADT on bone health by comparing longitudinal changes in BMD between prostate cancer patients with and without bone metastases. A single-center observational study was conducted from February 2020 to January 2023 at Kobe University Hospital. BMD at the lumbar vertebrae, total hip, and femoral neck was measured at baseline, 6, and 12 months using dual-energy X-ray absorptiometry. Bones were classified into Metastatic Site (with metastases), Non-metastatic Sites (from patients with bone metastases), and Control (patients without metastases) groups. All patients received luteinizing hormone-releasing hormone antagonists or agonists plus oral ARSI or bicalutamide for 1 year. Among the 78 patients, 35, 110, and 245 bones were classified into the Metastatic Site group, Non-metastatic Sites group, and Control group, respectively. The Metastatic Site group exhibited significantly higher T-scores compared with the other groups (P < 0.001). Repeated measures analysis revealed a statistically significant reduction in T-scores over time across all groups (P < 0.001). However, no significant interaction was observed between group classification and time (P = 0.817). The present study demonstrates that BMD changes at non-metastatic sites in patients with bone metastases are similar to those in patients without metastases. Monitoring BMD at non-metastatic sites may provide valuable insights into ADT's effects on bone health in prostate cancer patients.

A Phase 2 Trial of Radium223 and Stereotactic Ablative Radiotherapy in Hormone-Naïve Men with Oligometastatic Prostate Cancer to Bone: The RadSABR study.

We hypothesized that treatment with Radium223 (Ra223) and Stereotactic Ablative Radiotherapy (SABR) in patients with bone-only metachronous oligometastastic hormone-sensitive prostate cancer (moHSPC) could safely delay the start of androgen deprivation therapy (ADT) and maintain quality of life (QoL). This prospective trial included twenty men with moHSPC and ≤5 bone-only metastases who previously had definitive treatment to the prostate and pelvic lymph nodes. Eligibility criteria were testosterone ≥ 100 ng/dL and metastases validated by conventional imaging. Exclusion criteria were post-initial treatment LHRH therapy or N1 disease at bone metastasis diagnosis. Treatment included six cycles of Ra223 and SBRT (30 Gy in five fractions). Bone scans and PSA levels were monitored regularly. The primary endpoint was freedom from ADT (FFAdt) use at 15 months in ≥20% of patients. Patients were followed for 2 years, with clinically significant PRO changes defined as >1/2 standard deviation from baseline. Statistical analyses used Wilcoxon rank sum, Pearson's Chi2 tests, and univariate Cox regression, with significance set at P<0.05 RESULTS: The median number of Ra223 cycles was six. FFAdt at 15 and 24 months was 50.0% and 40.0%, respectively (p<0.001). Eleven (55%) and five (25%) patients had PSA declines exceeding 50% and 90%, respectively, with two patients achieving undetectable PSA levels (<0.01) at two years. No significant changes were observed in any PRO QoL domains. Two patients had grade 3 SREs, and grade 2+ events attributed to Ra223 and EBRT were observed in four and two patients, respectively. In this phase II trial, the initial use of Ra223 and SABR for moHSPC significantly delayed ADT use compared to historical controls. The therapy is well tolerated, preserves QoL, and can lead to undetectable PSA levels at two years.

Long-term Outcomes and Prognostic Impact of Residual Cancer Burden After Intensified Neoadjuvant Therapy in High-risk Prostate Cancer.

Long-term outcomes and the prognostic impact of the extent of residual disease after neoadjuvant therapy (NAT) with androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI) before radical prostatectomy (RP) for high-risk localized prostate cancer (HRLPC) are not known. We analyzed data for patients treated in five trials evaluating 6 mo of ARPI NAT for HRLPC at our institution between 2006 and 2018. Residual cancer burden (RCB) was quantitated as the calculated tumor volume adjusted for cellularity in the primary tumor. The primary outcome was metastasis-free survival (MFS) according to conventional imaging. We explored RCB categories using the Contal-O'Quigley method to distinguish high- and low-risk groups for MFS. Among 218 eligible patients, median prostate-specific antigen at diagnosis was 8ng/ml, 42 (20%) had cT3-4 disease, and 154 (71%) had a biopsy Gleason score of 8-10. At RP, 24 (11%) had a pathologic complete response and median RCB was 0.05 cm3 (interquartile range 0.00-0.32). By median follow-up of 5 yr, 45 patients had developed metastases and 11 died; the 5-yr MFS rate was 83% (95% confidence interval [CI] 77-88%). On multivariable analysis, higher RCB was associated with poorer MFS (hazard ratio 1.21, 95% CI 1.01-1.47). The 5-yr MFS rates were 100%, 90% (95% CI 72-97%), 82% (95% CI 73-88%), and 63% (95% CI 40-79%) for patients with RCB-0 (a pathologic complete response or no residual disease), RCB-1 (<0.003cm3), RCB-2 (0.003-0.672cm3), and RCB-3 (≥0.672cm3), respectively. The key limitation is lack of a validation cohort. The 5-yr MFS rate for patients treated with ARPI NAT before RP for HRLPC was 83%. The depth of pathologic response, evaluated as the RCB, was highly prognostic for MFS. RCB could be used to guide NAT and post-NAT adjuvant trials in HRLPC.

The Benefit of Short-Term Androgen Deprivation Therapy with Radiotherapy for Intermediate-Risk Prostate Cancer.

A previous, individual patient-level meta-analysis of randomized controlled trials (RCTs) demonstrated the overall survival (OS) benefit of short-term androgen deprivation therapy (ST-ADT) when delivered with radiotherapy for the subset of patients with intermediate-risk prostate cancer (IR-PCa). However, due to inclusion criteria, several studies such as NRG/RTOG 0815, GETUG-14, and DFCI 95-096 were excluded. Thus, we conduct the present analysis, inclusive of all studies to define the current role for ST-ADT in IR-PCa. A systematic review was conducted of phase III RCTs published or presented between 1/1980 and 10/2024 which profiled the comparative efficacy of radiotherapy ± ST-ADT in patients with IR-PCa. A study-level, random-effects meta-analysis was performed. The primary endpoint of this meta-analysis was OS, with secondary endpoints of time-to-biochemical failure (BF) ± biochemical-progress-free survival (bPFS). Meta-regression was utilized to explore trial-level factors associated with treatment effects. Synthetic individual patient-level OS data was pooled for confirmation and used to estimate the relative and absolute survival benefit. Seven RCTs (NRG/RTOG 9408, DFCI 95-096, TROG 96.01, PCS III, EORTC 22991, NRG/RTOG 0815, and GETUG-14) reporting outcomes of 6,279 patients were identified. The pooled HROS, HRBF, and HRBF+bPFS were 0.88 (95% confidence interval [CI]: 0.79-0.97; p = 0.01), 0.50 (95% CI: 0.37-0.68; p<0.001), and 0.54 (95% CI: 0.46-0.65; p<0.001), respectively. ST-ADT duration, RT dose, and Gleason score trial population composition were each associated with an increased benefit of ST-ADT for biochemical disease control (all p<0.05) but not for OS (all p>0.05). Pooling of simulated, patient-level data confirmed the presence of a survival benefit (HROS: 0.85 [95% CI: 0.76-0.96], log-rank p = 0.021), corresponding to an absolute survival benefit of 5% benefit at 10 years. The present analysis confirms current knowledge that ST-ADT improves both OS and PSA-based outcomes for unselected patients with IR-PCa to a clinically significant degree.

Major adverse cardiovascular events among Black and White Veterans receiving androgen deprivation therapy for prostate cancer: a retrospective cohort study

BackgroundAndrogen deprivation therapy (ADT) is the cornerstone treatment strategy for men diagnosed with high-risk prostate cancer (PC) but may increase risk for major adverse cardiovascular events (MACE). We examined whether men treated with ADT and radiation therapy (ADT + RT) developed MACE at a higher rate than men receiving RT alone. Secondly, we sought to determine if Black men receiving RT + ADT developed MACE at a higher rate than White men.MethodsThis retrospective cohort study examined time to diagnosis of MACE among Veterans with PC. We used a 1:1 propensity score matching process to determine whether treatment type (ADT + RT vs. RT alone), race (Black vs. White men) or having a previous diagnosis of a cardiometabolic disease (CMD) were associated with differences in the rate at which men develop MACE.ResultsVeterans with PC were White (68%) and Black (32%). At PC diagnosis, the mean age was 65.9 years. The majority had stage 2 disease (83.0%) classified as intermediate risk (43.1%). Treatment-matched models showed men receiving ADT + RT were less likely to develop MACE when they no pre-existing CMD. Men treated with ADT + RT or RT alone had significantly increased risks of MACE is they had pre-existing CMD. Black men had the same risk of MACE as non-Hispanic Whites.ConclusionsPreexisting CMD and multimorbidity are significant risks for MACE among men treated for PC within the VA healthcare system whether treated with ADT + RT or with RT alone, highlighting the importance pretreatment optimization of comorbidities.

The correlation between the expression of androgen receptor splice variant-7 (AR-V7) protein with the time of occurrence of castration-resistant prostate cancer and overall survival in prostate cancer in Indonesian population

IntroductionProstate cancer follows a natural trajectory characterized by genetic alterations that transform initially hormone-sensitive cancer cells into castration-resistant prostate cancer (CRPC), which is associated with high mortality. This study endeavours to elucidate the predictive role of androgen receptor splice variant 7 (AR-V7) protein expression in determining the time to CRPC onset and overall survival in prostate cancer patients.MethodsThis retrospective cohort study utilized paraffin-embedded tissue block samples collected from prostate cancer patients undergoing Androgen Deprivation Therapy at Dr. Sardjito General Hospital between 2016 and 2022 (n = 47). AR-V7 protein expression was assessed via immunohistochemistry. Time to CRPC and overall survival were subjected to Log- Rank analysis and Cox regression.ResultsPatients exhibiting AR-V7 + protein expression experienced a considerably shorter time to CRPC onset compared to those with AR-V7-expression (21.13 vs. 40.05 months; p-value = 0.020). In the assessment of overall survival, patients with AR-V7 + protein expression demonstrated significantly poorer overall survival rates in contrast to those with AR-V7-expression (17.00 vs. 22.00 months; p = 0.00).ConclusionsDiminished AR-V7 + protein expression emerges as a predictive indicator for a shortened time to CRPC onset. Moreover, AR-V7 protein expression holds prognostic value in predicting overall survival among prostate cancer patients.

Utilization of Radical Prostatectomy Versus Radiation Therapy for Gleason Grade Group 5 Prostate Cancer Before and After USPSTF Grade D Recommendation Against Prostate-Specific Antigen Screening in 2012.

The 2012 United States Preventive Services Task Force (USPSTF) Grade D recommendation against prostate-specific antigen (PSA) screening has resulted in a shift to higher-stage prostate cancer (PC) at diagnosis. We evaluate the utilization of radical prostatectomy (RP) versus radiation therapy (RT) in the US for Gleason grade group 5 (GG5) prostate cancer before and after 2012. We identified 34,011 men with localized GG5 PC undergoing primary therapy with (1) RP or (2) RT + androgen deprivation therapy (ADT) between 2004 and 2017 from the National Cancer Database. The chi-square test was used to compare the relative use of RP and RT before versus after 2012. Annual use of RP versus RT from 2004 to 2017 was compared using Cochran-Armitage test for trend. We modeled the effect of treatment year on the use of RP using multivariable logistic regression. Across all centers, the use of RP increased from 31% to 41% (p for trend < 0.001). 2012 was associated with significant inflection for increase in RP use in all centers. There was an increased odds of receiving RP after 2012 (adjusted OR 1.34, 95% CI 1.28-1.40, p < 0.001). Utilization of RP for GG5 PC has significantly increased in the United States over the past decade. It remains unknown if outcomes may be compromised in this group of high-risk men, many of whom require post-prostatectomy RT and/or ADT. Prospective comparison of RP versus RT + ADT for GG5 PC are needed to determine optimal treatment for these patients.

Trillin inhibits MAP3K11/NF-κB/COX-2 signaling pathways through upregulation of miR-145-5p in castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) presents a significant challenge in treatment following androgen deprivation therapy. This study evaluates Trillin, a compound with antioxidant and anti-inflammatory properties, for its therapeutic potential against CRPC. Using DU145 and PC3 cell lines and a mouse xenograft model, we demonstrate that Trillin effectively inhibits CRPC cell viability, proliferation, migration, and invasion while promoting apoptosis and cell-cycle arrest. Mechanistic investigations reveal that Trillin disrupts NF-κB/COX-2 signaling by downregulating MAP3K11 and COX-2 and inhibiting the nuclear translocation of NF-κB subunits. Additionally, Trillin enhances the expression of miR-145-5p, further modulating pathways critical for CRPC progression. These findings suggest that Trillin may offer a promising alternative approach for targeting CRPC, highlighting its potential as a therapeutic agent to improve patient outcomes.

Salvage radiotherapy with volumetric modulated arc therapy (VMAT) for recurrent prostate cancer after high-intensity focused ultrasound (HIFU): A large French retrospective series and literature review.

Although not validated as a standard treatment, high-intensity focused ultrasound (HIFU) is increasingly used in the management of localized prostate cancer (PCa). In case of recurrence after HIFU, treatment is currently not standardized. Our aim was to evaluate normofractionated (NFRT) and hypofractionated (HFRT) salvage radiotherapy (RT) using volumetric modulated arctherapy (s-VMAT) with doses used in first-line management of localised PCa. We identified all patients with local or locoregional recurrence after HIFU treated with s-VMAT in 3 RT centres between 2014 and 2023. We evaluated acute and late toxicity and oncological outcomes. Fifty-six patients were identified. Median age at recurrence was 75 (70-80) years. Median time between HIFU and s-VMAT was 26.5 months (13.9-47.2). S-VMAT was delivered to the prostate only in 35 (62.5 %) patients and to the prostate and pelvis in 21 (37.5 %) patients. NFRT and HFRT were delivered in 46 (82.1 %) and 10 (17.9 %) patients, respectively. Androgen deprivation therapy (ADT) was given to 27 (48.2 %) patients. Eighteen (32 %) and four (7 %) patients reported an acute grade 2 genitourinary (GU) and gastrointestinal (GI) adverse even (AE), respectively. Two patients presented with a late grade 2 GU AE, and one with a late grade 2 GI AE. No grade 3 + toxicity was reported. With a median follow-up of 19.5 months (12 - 47), no patient had a biochemical, local or distant relapse. This is the largest series of salvage RT after HIFU using VMAT and escalated doses (78-80 Gy/39-40Fr., or 60 Gy/20Fr.). Acute toxicity was acceptable and late AEs were few. Longer follow-up is required to assess efficacy. Overall, available series suggest that salvage RT could represent a valuable option in the treatment of relapses after HIFU.

MiRNA Signatures as Predictors of Therapy Response in Castration-Resistant Prostate Cancer: Insights from Clinical Liquid Biopsies and 3D Culture Models

Background/Objectives: Prostate cancer (PCa) patients who do not respond to androgen deprivation therapy (ADT), referred to as castration-resistant prostate cancer (CRPC), remain a clinical challenge due to confirm the aggressive nature of CRPC and its resistance to conventional therapies. This study aims to investigate the potential of microRNAs (miRNAs) as biomarkers for predicting therapeutic response in CRPC patients. Methods: We performed miRNA and mRNA expression analyses using publicly available datasets and applied 3D cell culture models to replicate more physiologically relevant tumor conditions. Genetic analysis techniques were employed on publicly available data, and expression profiles from 3D cell culture models were examined. Results: Eighteen miRNAs with differential expression were identified between patients who responded favorably to abiraterone therapy (responders) and those with advanced CRPC (non-responders). Specifically, miRNAs such as hsa-miR-152-3p and hsa-miR-34a-3p were found to be associated with critical pathways, including TGF-β signaling and P53, which are linked to therapeutic resistance. Several miRNAs were identified as potential predictors of treatment efficacy, including therapies like abiraterone. Conclusions: These results indicate that miRNAs could serve as non-invasive biomarkers for predicting therapeutic outcomes, facilitating a more personalized approach to CRPC treatment. This study provides a novel perspective on treatment strategies for CRPC, emphasizing the role of miRNAs in improving therapeutic precision and efficacy in this complex disease.

Acceptability of a nurse-led survivorship intervention for men with prostate cancer receiving Androgen Deprivation Therapy: A qualitative exploratory study

Acceptability of a nurse-led survivorship intervention for men with prostate cancer receiving Androgen Deprivation Therapy: A qualitative exploratory study

Immunohistochemical Analysis of Androgen Receptor Expression Predicts the Prognosis of Metastatic Castration-Sensitive Prostate Cancer Patients Receiving Abiraterone Acetate.

The efficacy of abiraterone acetate varies among patients with high-risk metastatic castration-sensitive prostate cancer (mCSPC). Both androgen receptor (AR) and cytokeratin 18 (CK18) are markers of the luminal lineage of prostate cancer, and their expression levels have been suggested to affect the response to androgen deprivation therapy (ADT). This study aimed to predict the efficacy of abiraterone acetate in high-risk mCSPC via immunohistochemical staining of biopsy specimens obtained at the time of prostate cancer diagnosis. We retrospectively analyzed 44 patients treated with abiraterone acetate in combination with ADT. AR and CK18 expression in prostate biopsy specimens were assessed using immunohistochemical staining. AR and CK18 staining was not significantly associated with overall survival (OS). However, low AR staining was significantly associated with a shorter time to castration-resistant prostate cancer (TTCRPC) compared with high AR staining (log-rank test, p = 0.018). Similarly, low CK18 staining was significantly associated with a shorter TTCRPC compared with high CK18 staining (log-rank test, p = 0.037). Immunohistochemical analysis of AR or CK18 expression in biopsy specimens may serve as a predictive biomarker of high-risk mCSPC treated with abiraterone acetate. None.

Androgen Deprivation Therapy: Mitochondrial Dysfunction and Metabolic Impacts in Prostate Cancer

Androgen Deprivation Therapy: Mitochondrial Dysfunction and Metabolic Impacts in Prostate Cancer

Comparative Insights into the Role of Sex Hormones in Glaucoma Among Women and Men.

Baseline differences in sex hormone levels between males and females influence tissues including the brain and eye. To investigate the effects of estrogens and androgens on ocular physiology and glaucoma, we review the current literature on the influence of primary sex hormones on ocular function, glaucoma incidence and related parameters like intraocular pressure (IOP) at physiologic levels and related to hormone therapies in men and women. These articles reveal activity of estrogen, testosterone, and progesterone within ocular tissues including the retinal pigment epithelium and ciliary epithelium where they likely influence glaucoma pathophysiology through effects on ocular blood flow and aqueous outflow. A growing body of evidence demonstrates a protective role of estrogen in glaucoma. With fluctuations across a woman's lifetime through menstrual phases, pregnancy, and menopause, the general association seen is a lower risk of glaucoma and lower IOP with higher estrogen. Exogenous hormones in the form of oral contraceptive pills and hormone replacement therapy also appear to affect glaucoma risk, although published findings are inconsistent. Few studies have reported a positive association between IOP and serum testosterone, and men treated with androgen deprivation therapy have shown a reduced risk of glaucoma while masculinizing hormone therapies at supra-physiologic testosterone levels have significantly increased IOP. Sex hormone perturbations affect components of glaucoma pathogenesis including IOP and ocular blood flow and overlap with known risk factors like age and sex. Standardized studies are needed to further elucidate the roles of estrogen and testosterone in glaucoma risk and progression.

Genomic biomarkers of survival in patients with metastatic hormone-sensitive prostate cancer undergoing intensified androgen deprivation therapy.

Androgen deprivation therapy intensification (ADTi) with androgen receptor pathway inhibitors (ARPI), docetaxel or both has been shown to improvesurvival outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC). Currently, baseline tumor genomic markers have no role in clinical decision-making in patients with mHSPC. In this IRB-approved retrospective study, patients diagnosed with mHSPC who underwent comprehensive genomic profiling from primary tissue or metastatic sites and treated with ADTi were included. Genomic alterations with an incidence ≥5% were included in the analysis. A total of 276 patients were eligible and included in the study. In the multivariable analysis, TP53 (HR 1.71, 95% CI 1.17-2.49, p = 0.006), RB1 (HR 2.32, 95% CI 1.28-4.18, p = 0.006), PTEN (HR 1.74, 95% CI 1.12-2.7, p = 0.014), and BRCA2 (HR 2.64, 95% CI 1.42-4.92, p = 0.003) were associated with significantly shorter PFS, while TP53 (HR 1.63, 95% CI 1.00-2.64, p = 0.049), RB1 (HR 4.5, 95% CI 2.32-8.70, p < 0.001), and PTEN (HR 2.4, 95% CI 1.38-4.2, p = 0.003) were associated with significantly worse OS. This is one of the largest studies to show the association of baseline tumor genomic markers with survival in patients with mHSPC treated with ADTi. Upon external validation, these results may aid in developing a clinical-genomic risk stratification model, patient counseling, and prognostication.

The prognostic and neuroendocrine implications of SLC25A29-mediated biomass signature in prostate cancer.

Dysregulated solutes are linked to cancer progression, with associated carriers being potential targets for prognosis and treatment. Androgen deprivation therapy (ADT) is essential for prostate cancer (PCa) progression, but secondary resistance often leads to androgen-independent tumor growth, necessitating new prognostic biomarkers. Transcriptome-based datasets identify SLC25A29, an arginine carrier, as upregulated in PCa, correlating with metastatic features and serving as a high-risk prognostic factor, particularly in castration-resistant prostate cancer (CRPC). Molecular simulations indicate that SLC25A29-mediated pathways contribute to mitochondrial metabolism and redox homeostasis, implicating POLD1 regulation and suggesting a link to ferroptosis. Further analysis reveals that SLC25A29 may transactivate POLD1 via E2F1, as shown by RNA-seq profiling of E2F1 knockdown in CRPC-related cells, which demonstrated reduced POLD1 expression. Clinical and cellular studies confirm that SLC25A29, E2F1, and POLD1 levels positively correlate with pathological features, with their downstream effectors serving as prognosis signatures. The SLC25A29/E2F1/POLD1 axis is associated with neuroendocrine PCa (NEPC) development, indicating its role in response to androgen receptor inhibition. Downregulation of E2F1 not only decreases POLD1 levels but also reduces NEPC-related markers. These findings support the SLC25A29/E2F1/POLD1 axis as a prognostic tool for CRPC and NEPC, and targeting E2F1 may offer a therapeutic strategy to disrupt SLC25A29-mediated PCa progression.

The interplay between acute and late toxicity among patients receiving prostate radiotherapy: an individual patient data meta-analysis of six randomised trials.

The association between acute and late toxicity following prostate radiotherapy has not been well studied using data from multiple randomised clinical trials and fractionation schedules. We aimed to characterise the relationship between acute and late genitourinary and gastrointestinal toxicity among patients receiving conventionally fractionated or moderately hypofractionated prostate radiotherapy. This was an individual patient data meta-analysis that identified randomised phase 3 trials of conventionally fractionated or moderately hypofractionated prostate radiotherapy in the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) Consortium that had individual-level acute and late toxicity data available and were available before Dec 1, 2023. Trials without individual patient data were excluded. Data were provided to MARCAP by study investigators. The associations between acute (≤3 months after radiotherapy) and late (>3 months after radiotherapy) grade 2 or greater genitourinary and gastrointestinal toxicities were assessed using adjusted generalised linear mixed models (adjusted for age, androgen deprivation therapy status, type of radiotherapy, radiation dose, and radiation schedule). In the subset of trials that collected Expanded Prostate Cancer Index Composite quality of life (QOL) evaluations, the association between acute genitourinary and gastrointestinal toxicity and decrements at least twice the minimal clinically important difference (MCID) for urinary and bowel QOL were also evaluated. Six of 26 available trials met all the eligibility criteria. 6593 patients were included (conventionally fractionated: n=4248; moderately hypofractionated: n=2345). Median follow-up was 72 months (IQR 61-94). Acute grade 2 or greater genitourinary toxicity was associated with both late grade 2 or greater genitourinary toxicity (odds ratio 2·20 [95% CI 1·88-2·57], p<0·0001) and decrement at least twice the MCID in urinary QOL (1·41 [1·17-1·68], p=0·0002). Acute grade 2 or greater gastrointestinal toxicity was associated with both late grade 2 or greater gastrointestinal toxicity (2·53 [2·07-3·08], p<0·0001) and decrement at least twice the MCID in bowel QOL (1·52 [1·26-1·83], p<0·0001). Acute toxicity following prostate radiotherapy was statistically significantly associated with late toxicity and with decrement in patient-reported QOL metrics. These data support efforts to evaluate whether interventions that reduce acute toxicity ultimately reduce the risk of late toxicity. National Institutes of Health and US Department of Defense.

Androgen deprivation therapy does not increase rates for reintervention, complication, or infection in primary penile implant or artificial urinary sphincter surgery: a retrospective cohort study from the TriNetX network.

Prostate cancer treatment-related erectile dysfunction and stress urinary incontinence are commonly treated with inflatable penile prosthesis (IPP) or artificial urinary sphincter (AUS). Given the association with androgens and penile/urethral health, we aim to evaluate whether patients on androgen deprivation therapy (ADT) undergoing IPP or AUS surgery are at increased risk for reintervention, complication, or infection. We queried the TriNetX database for adult males receiving IPP or AUS. The ADT cohort included those on ADT 3 months before or any time after surgery. We performed sub-analysis for leuprolide and bicalutamide. Cohorts and outcomes were defined by Current Procedural Terminology and International Classification of Diseases codes. Propensity score matching was performed using age, prostate cancer, history of prostatectomy, and history of radiation. Outcomes were reintervention (revision, removal, or replacement), infection, and complication. Analytics were performed in March 2024. 13,432 patients received an IPP and 5676 received an AUS, 465 and 745 of whom were on ADT, respectively. The only significant AUS analysis was for patients on abiraterone having fewer reinterventions (10.5% vs 20.8%, RR = 0.50 [0.29, 0.88]). Patients receiving an IPP with ADT had fewer reinterventions (7.2% vs 12%, RR = 0.60 [0.39, 0.92]) and complications (12.7% vs 18.5%, RR = 0.68 [0.49, 0.95]). Those on a GnRH agonist had fewer reinterventions (7.4% vs 11.7%, RR = 0.63 [0.41, 0.98]) for IPP. Patients receiving an IPP on bicalutamide had fewer reinterventions ( <5.2%* vs 10.8%, RR = 0.48 [0.23, 0.99]) and on leuprolide had fewer complications (12.2% vs 19.3%, RR = 0.63 [0.43, 0.91]). The remainder of analyses showed no significant differences. Patients with IPP or AUS do not fare worse on ADT. Further evaluation into the duration of ADT may provide clinical context, but based on these results, ADT should not limit implant surgery.

External beam radiation therapy versus radical prostatectomy for high-risk prostate cancer: protocol of the RECOVER study

BackgroundThis paper describes the rationale and design of the RECOVER study. Currently, there is no consensus regarding the optimal treatment for high-risk, non-metastatic prostate cancer (PCa). The study primarily aims to evaluate and compare the impact of treatment with robot-assisted radical prostatectomy (RP) versus external beam radiation therapy (EBRT) with androgen deprivation therapy (ADT) for men with high-risk, non-metastatic PCa regarding health-related quality of life (HRQoL) and functional outcomes. Secondary objectives are progression-free survival (PFS), distant metastasis-free survival (DMFS), costs and cost-effectiveness.MethodsThe RECOVER study is a comparative effectiveness study that prospectively includes newly diagnosed high-risk (cT3a-bN0M0, ISUP-grade ≥ 4 and/or PSA > 20 ng/mL), non-metastatic PCa patients. Four Dutch prostate cancer networks, comprising 29 hospitals, are currently participating in the study. Patient reported outcomes are collected before treatment initiation, 12 months and 36 months after treatment initiation and include the EORTC-QLQ-C30, the EPIC-26, an adapted version of the SCQ, an adapted version of the iMTA Productivity Cost Questionnaire and several specific questions regarding patient characteristics, treatment of PCa specific complaints and health resources used. Clinical data regarding patient-, tumor- and treatment characteristics and oncological outcomes are collected up to 5 years after diagnosis. For sufficient power, patient reported outcomes of 471 patients must be collected 36 months after treatment initiation. Descriptive statistics and mixed-effects models are used to assess differences in HRQoL and functional outcomes over time between the patients treated with radical prostatectomy versus EBRT (+ ADT). Inverse probability of treatment weighting or the g-formula are used to adjust for confounding covariates associated with treatment. Secondary endpoints PFS and DMFS are evaluated using a competing risk analysis and cost-utility and budget-impact analyses will be performed to determine cost and cost-effectiveness.DiscussionAn observational prospective design was chosen since a randomized controlled trial comparing surgery and radiotherapy was not deemed feasible. This study evaluates effectiveness of treatment in a routine clinical setting (with adjustment for confounding) and its findings will enhance patients’ and healthcare professionals’ awareness for the impact of both treatment modalities on (long-term) daily functioning and HRQoL and aid treatment decision making.Trial registrationThis study is registered at ClinicalTrials.gov (NCT05931419).