Use Of Androgen Deprivation Therapy Research Articles

Risk of prostate cancer death in men diagnosed with prostate cancer at cystoprostat-ectomy. A nationwide population-based study.

One out of three men who undergo cystoprostatectomy for bladder cancer is diagnosed with incidental prostate cancer (PCa) at histopathological examination. Many of these men are PSA tested as part of their follow-up, but it is unclear if this is needed. The aim of this study was to assess the risk of PCa death in these men and the need of PSA-testing during follow-up. Between 2002 and 2020, 1,554 men were diagnosed with PCa after cystoprostatectomy performed for non-metastatic bladder cancer and registered in the National Prostate Cancer Register (NPCR) of Sweden. We assessed their risk of death from PCa, bladder cancer and other causes up to 15 years after diagnosis by use of data in The Cause of Death Register. The use of androgen deprivation therapy (ADT) as a proxy for PCa progression was assessed by fillings in The Prescribed Drug Register. Fifteen years after diagnosis, cumulative incidence of death from PCa was 2.6% (95% CI 2.3%-2.9%), from bladder cancer 32% (95% CI: 30%-34%) and from other causes 40% (95% CI: 36%-44%). Only 35% of men with PCa recorded as primary cause of death in The Cause of Death Register had started ADT before date of death, indicating sticky-diagnosis bias with inflated risk of PCa death. For a large majority of men diagnosed with incidental PCa at cystoprostatectomy performed for bladder cancer, the risk of PCa death is very small so there is no rationale for PSA testing during follow-up.

Impact of the coronavirus disease pandemic on robot-assisted radical prostatectomy and urologists' treatment behaviors: A single tertiary center retrospective study.

To assess whether the coronavirus disease (COVID-19) pandemic affected the outcomes of robot-assisted radical prostatectomy (RARP) and urologists' treatment behaviors. We retrospectively examined the medical records of 208 patients who had undergone RARP between August 2017 and December 2022. We compared the rate of preoperative androgen deprivation therapy (ADT), waiting period for RARP, patients' baseline characteristics and quality of life (QOL), proportion of adverse pathology on the RARP specimen, rate of Gleason grade group upgrading from biopsy to the RARP specimen, and prostate-specific antigen (PSA) recurrence-free survival between the pre-pandemic and pandemic groups. The rate of preoperative ADT was significantly higher during than before the COVID-19 pandemic (13.7% vs. 1.9%; p = 0.002). The baseline physical and mental QOL scores did not differ significantly between the groups. The proportion of D'Amico low-risk patients was significantly lower (13.6% vs. 1.2%, p = 0.005) and waiting period for RARP was significantly shorter (median 3.5 months vs. 4.0 months, p = 0.016) in the pandemic group than in the pre-pandemic group. There was no significant difference in the proportion of adverse pathology between the groups (p = 0.104); however, the upgrading rate was significantly higher in the pre-pandemic group (p = 0.002). There was no significant difference in PSA recurrence-free survival between the groups (log-rank, p = 0.752). The COVID-19 pandemic did not adversely affect the oncologic outcomes of RARP and QOL before RARP. However, it caused urologists to increase the use of preoperative ADT and to reserve RARP for higher-risk cases.

Differences in real-world outcomes by risk classification for localized prostate cancer patients after radiation therapy.

Limited real-world evidence exists on the long-term clinical outcomes of patients with localized prostate cancer (LPC) who received external beam radiation therapy (EBRT) as the initial treatment. This study evaluated clinical outcomes of US patients with high-risk LPC (HR-LPC) and low/intermediate-risk LPC (LIR-LPC) who received EBRT. This retrospective study using Surveillance, Epidemiology, and End Results-Medicare linked data from 2012 to 2019 included patients ≥ 65 years old who received EBRT as initial therapy. Baseline patient characteristics were summarized, metastasis-free survival (MFS), overall survival, and time to initiation of advanced prostate cancer treatment were compared using Kaplan-Meier (KM) and adjusted Cox proportional hazard (PH) models. 5-year survival probabilities stratified by race/ethnicity (non-Hispanic [NH] White, NH Black, NH Asian, and Hispanic) were assessed. Of 11,313 eligible patients, 41% (n = 4600) had HR-LPC and 59% (n = 6713) had LIR-LPC. Patient characteristics for both groups were comparable, with mean age at EBRT initiation > 70 years, 86% white, and mean follow-up time >40 months. More patients in the HR-LPC than LIR-LPC groups (78% vs 34%) had concurrent androgen deprivation therapy use and for a longer duration (median 10.4 months vs. 7.4 months). A higher proportion of HR-LPC patients developed metastasis, died, or received advanced prostate cancer treatment. Adjusted Cox PH survival analyses showed significantly (p < 0.0001) higher risk of mortality (hazard ratios[HR], 1.57 [1.38, 2.34]), metastasis or death (HR, 1.97 [1.78, 2.17]), and advanced prostate cancer therapy use (HR, 2.57 [2.11, 3.14]) for HR-LPC than LIR-LPC patients. Within 5 years after the initial EBRT treatment, 18%-26% of patients with HR-LPC are expected to have died or developed metastasis. The 5-year MFS rate in the HR-LPC group was lower than the LIR-LPC group across all racial/ethnic subgroups. NH Black patients with HR-LPC had the highest all-cause mortality rate and lowest rate of receiving advanced prostate cancer treatment, compared to other racial/ethnic subgroups. This real-world study of clinical outcomes in patients with LPC treated with EBRT suggests substantial disease burden in patients with HR-LPC and highlights the need for additional treatment strategies to improve clinical outcomes in patients with HR-LPC.

Real-world treatment patterns and medical costs of prostate cancer patients in Switzerland – A claims data analysis

BackgroundProstate cancer (PC) is the most prevalent cancer in men in Switzerland. However, evidence on the real-world health care use of PC patients is scarce. The aim of this study is to describe health care utilization, treatment patterns, and medical costs in PC patients over a period of five years (2014–2018). MethodWe used routinely collected longitudinal individual-level claims data from a major provider of mandatory health insurance in Switzerland. Due to the lack of diagnostic coding in the claims data, we identified treated PC patients based on the treatments received. We described health care utilization and treatment pathways for patients with localized and metastatic PC. Costs were calculated from a health care system perspective. ResultsA total of 5591 PC patients met the inclusion criteria. Between 2014 and 2018, 1741 patients had outpatient radiotherapy for localized or metastatic PC and 1579 patients underwent radical prostatectomy. 3502 patients had an androgen deprivation therapy (ADT). 9.5% of these patients had a combination therapy with docetaxel, and 11.0% had a combination with abiraterone acetate. Docetaxel was the most commonly used chemotherapy (first-line; n = 413, 78.4% of all patients in chemotherapy). Total medical costs of PC in Switzerland were estimated at CHF 347 m (95% CI 323–372) in 2018. ConclusionMost PC patients in this study were identified based on the use of ADT. Medical costs of PC in Switzerland amounted to 0.45% of total health care spending in 2018. Treatment of metastatic PC accounted for about two thirds of spending.

Unpacking overuse of androgen deprivation therapy for prostate cancer to inform de-implementation strategies

BackgroundMany men with prostate cancer will be exposed to androgen deprivation therapy (ADT). While evidence-based ADT use is common, ADT is also used in cases with no or limited evidence resulting in more harm than benefit, i.e., overuse. Since there are risks of ADT (e.g., diabetes, osteoporosis), it is important to understand the behaviors facilitating overuse to inform de-implementation strategies. For these reasons, we conducted a theory-informed survey study, including a discrete choice experiment (DCE), to better understand ADT overuse and provider preferences for mitigating overuse.MethodsOur survey used the Action, Actor, Context, Target, Time (AACTT) framework, the Theoretical Domains Framework (TDF), the Capability, Opportunity, Motivation–Behavior (COM-B) Model, and a DCE to elicit provider de-implementation strategy preferences. We surveyed the Society of Government Service Urologists listserv in December 2020. We stratified respondents based on the likelihood of stopping overuse as ADT monotherapy for localized prostate cancer (“yes”/“probably yes,” “probably no”/“no”), and characterized corresponding Likert scale responses to seven COM-B statements. We used multivariable regression to identify associations between stopping ADT overuse and COM-B responses.ResultsOur survey was completed by 84 respondents (13% response rate), with 27% indicating “probably no”/“no” to stopping ADT overuse. We found differences across respondents who said they would and would not stop ADT overuse in demographics and COM-B statements. Our model identified 2 COM-B domains (Opportunity–Social, Motivation–Reflective) significantly associated with a lower likelihood of stopping ADT overuse. Our DCE demonstrated in-person communication, multidisciplinary review, and medical record documentation may be effective in reducing ADT overuse.ConclusionsOur study used a behavioral theory-informed survey, including a DCE, to identify behaviors and context underpinning ADT overuse. Specifying behaviors supporting and gathering provider preferences in addressing ADT overuse requires a stepwise, stakeholder-engaged approach to support evidence-based cancer care. From this work, we are pursuing targeted improvement strategies.Trial registrationClinicalTrials.gov, NCT03579680

The effect of dose-escalation radiotherapy with simultaneous-integrated-boost on the use of short-term androgen deprivation therapy in patients with intermediate risk prostate cancer.

To compare the biochemical failure (FFBF) and prostate cancer specific survival (PCSS) rates of patients with intermediate-risk prostate cancer (IR-PC) who were treated with 6 months of androgen deprivation therapy (ADT) with 78 Gy to the prostate, those treated with ADT and focal boost (FB) of 86 Gy to intraprostatic lesion (IPL) using the simultaneous-integrated boost (SIB) technique, and those treated with SIB alone. A retrospective analysis of 320 IR-PC patients treated between January 2012 and April 2021 was performed. Patients were divided into three groups based on their treatment arm: 78 + ADT (109 patients, 34.1%), 78/86 (102 patients, 31.8%), and 78/86 + ADT. Univariable and multivariable analyses were used to determine prognostic factors for FFBF and PCSS. Median follow-up was 8.8 years. The 8-year FFBF and PCSS rates were 88.6% and 99.0%. Patients who received ADT had significantly higher pretreatment PSA levels and clinical tumor stage. Disease progression occurred in 45 patients (7.3%) at a median of 41.9 months after definitive radiotherapy (RT). Younger age, positive core biopsy (PCB) ≥ 50%, and the absence of ADT were all independent predictors of poor FFBF in multivariate analysis, whereas patients with PCB < 50% who were also given ADT had better PCSS. Patients treated with 78/86 Gy alone had worse FFBF than those treated with 78 Gy and ADT (Hazard ratio [HR] = 3.39 [95% CI = 1.46-7.88]; p = 0.005), as well as than those treated with 78/86 Gy and ADT (HR = 3.21 [95% CI = 1.23-6.46]; p = 0.009). However, FB to IPL has no effect on PCSS in multivariable analysis. There was no significant difference between treatment groups in terms of acute and late Grade ≥2 genitourinary or gastrointestinal toxicity. Our findings demonstrated that patients who received 78/86 alone did worse than patients who received ADT with either 78 or 78/86 Gy. However, because IR-PC patients are so diverse, additional prospective trials are needed to validate our findings.

Cognitive effects of long-term androgen deprivation therapy in older men with prostate cancer.

Androgen deprivation therapy (ADT) is a common treatment for prostate cancer (PCa), with increasing numbers of men on ADT for longer. Limited evidence suggests ADT impacts cognition. This study addressed gaps in the literature by focusing on older men with PCa and assessing ADT usage longer than 1year. This study of 133 men ≥65years of age with PCa included two groups: (1) men on ADT for 1-3years (ADT-exposed), and (2) a comparison group of men with PCa not on ADT (ADT-unexposed). Group comparisons on individual neuropsychological test scores are reported, as well as effect sizes (Cohen's d). Half (n=67) of the sample was ADT-exposed and half (n=66) were unexposed. The average age was 72years, most were White, and over 50% had at least secondary education. There were no statistically significant differences between groups by age, race, or education. Unadjusted analyses showed the ADT-exposed group, compared with the ADT-unexposed group, performed significantly lower in domains of verbal learning (d=0.45-0.52, p=0.01 to <0.01), verbal recall (d=0.33-0.54, p=0.06 to <0.01), and possible effects in visuospatial construction (d=0.33, p=0.08 to 0.06). When controlling for age and education, similar patterns emerged. The ADT exposed-group performed significantly lower in domains of verbal learning (d=0.45-0.52, p=0.06 to 0.03) and verbal recall (d=0.33-0.54, p=0.11 to 0.03), and possible effects in visuospatial construction d=0.33, p=0.18 to 0.13. This study suggests long-term ADT exposure impacts verbal learning, verbal recall, and possibly visuospatial abilities in older men (≥65) with PCa. The potential cognitive effects of ADT should be discussed with older patients considering long-term use of ADT.

Image-guided moderately hypofractionated radiotherapy for localized prostate cancer: a multicentric retrospective study (IPOPROMISE)

BackgroundModerate hypofractionated radiotherapy is a treatment option for the cure of localized prostate cancer (PCa) patients based on the results of randomized prospective trials, but there is a clinical concern about the relatively short length of follow-up, and real-world results on outcome and toxicity based on cutting-edge techniques are lacking. The objective of this study is to present the long-term results of a large multicentric series.Materials and methodsWe retrospectively evaluated 1325 PCa patients treated with daily volumetric image-guided hypofractionated radiotherapy between 2007 and 2020 in 16 Centers. For survival endpoints, we used Kaplan–Meier survival curves and fitted univariate and multivariable Cox’s proportional hazards regression models to study the association between the clinical variables and each survival type.ResultsAt the end of the follow-up, 11 patients died from PCa. The 15-year values of cancer-specific survival (CSS) and biochemical relapse-free survival (b-RFS) were 98.5% (95%CI 97.3–99.6%) and 85.5% (95%CI 81.9–89.4%), respectively. The multivariate analysis showed that baseline PSA, Gleason score, and the use of androgen deprivation therapy were significant variables for all the outcomes. Acute gastrointestinal (GI) and genitourinary (GU) toxicities of grade ≥ 2 were 7.0% and 16.98%, respectively. The 15-year late grade ≥ 2 GI and GU toxicities were 5% (95%CI 4–6%) and 6% (95%CI 4–8%), respectively.ConclusionReal-world long-term results of this multicentric study on cutting-edge techniques for the cure of localized PCa demonstrated an excellent biochemical-free survival rate of 85.5% at 15 years, and very low rates of ≥ G3 late GU and GI toxicity (1.6% and 0.9% respectively), strengthening the results of the available published trials.

Mature results of a phase 2 pilot study of radium-223 and radiotherapy in untreated hormone-naïve men with oligometastatic prostate cancer to bone.

160 Background: We hypothesized that treatment with Radium-223 (Ra223) and to ≤5 sites of bony metastases could safely delay the time to start androgen deprivation therapy (ADT) and maintain quality of life (QoL). Methods: 20 men previously treated with surgery, radiation, or both for M0 PCa later developed ≤5 bone-only mets were eligible for this prospective trial. Inclusion: testosterone ≥ 100 ng/dL and mets on conventional bone scan, validated by a CT, MRI, or PET/CT. Exclusion: LHRH therapies after initial treatment or N1 disease at diagnosis of bone mets. Therapy was 6 cycles of Ra223 and SBRT (30 Gy in 5 fractions between cycles 1-2). Bone scan was performed at baseline and q3 months. PSA was evaluated monthly during the Ra223 course and q3 months after. Therapeutic effectiveness was defined as ≥20% of patients meeting the primary endpoint of freedom from ADT (FFAdt) use at 15 months. Discontinuation of study therapy occurred if: PSA rise &gt; 10% if baseline PSA &gt;20ng/ml, PSA&gt;20 if baseline PSA &lt;20 ng/ml, radiographic progression or a skeletal-related event (SRE). All endpoints were timed from the Cycle 1 radium date. Patients were followed for 2 years. Clinically significant changes in patient-reported outcome (PRO) measures were defined as &gt;1/2 standard deviation from the mean baseline value and were censored after the time of ADT use. Continuous and categorical covariates were compared using the Wilcoxon rank sum and Pearson’s Chi2 tests and univariate Cox regression. Statistical significance was considered at P&lt;0.05. Results: The median number of Ra223 cycles was 6. 6 patients had &lt;6 cycles (range 2-5) due to progression. FFAdt at 15 and 24 months was 50.0% and 40.0%, respectively (p&lt;0.001). Median time to ADT was 15 months. 11 (55%) and 5 (25%) patients had a PSA decline exceeding 50% and 90%, respectively. Two patients had undetectable (PSA&lt;0.01) at 2 years. There were no significant changes from baseline in any PRO QoL domain (physical functioning, anxiety, depression, fatigue, satisfaction with participation in social roles, sleep disturbance, and pain interference). There were 2 patients with Grade 3 SREs (bone fracture, pain). Grade 2+ events attributed as possible or likely to Ra-223 were seen in 4 patients (bone pain, fatigue, fracture, decreased WBC count, and other). Grade 2+ events attributed as possible or likely to EBRT were seen in 2 patients, including fatigue and other pain. No differences were noted for age, baseline PSA, days from primary treatment, NCCN risk group, TNM stage, ISUP grade group, BMI, or # of lesions in those who met or failed the primary endpoint (all p&gt;0.05). Conclusions: In this prospective pilot study, the first-line use of Ra223 and SBRT to conventionally imaged oligomets in hormone-naïve men resulted in a significant delay in ADT use compared to historical control. The therapy is well tolerated, maintains QoL, and may result in undetectable PSA. Clinical trial information: NCT03304418 .

Prostate-specific antigen (PSA) response among patients with metastatic castration-sensitive prostate cancer (mCSPC) initiated on apalutamide (APA) or abiraterone acetate (ABI) in real-world urology practices.

53 Background: Recently approved oral therapies APA and ABI (plus prednisone) are effective mCSPC treatments. Prior real-world evidence showed that, relative to ABI, patients who initiated APA had significantly higher rates of PSA decline ≥90% (PSA90), which has been associated with longer overall survival. The objective of this study was to compare PSA90 response among an enhanced cohort of patients with mCSPC initiated on APA or ABI. Methods: Electronic medical records from PPS Analytics including data from US community urology practices were linked with administrative claims from the Komodo Health Solutions Research Database. Androgen receptor signaling inhibitor (ARSI)-naïve patients with mCSPC with ≥12 months of pre-index clinical activity were selected into the APA or ABI cohort based on their first paid claim/dispensation on or after 17 Sep 2019 (index date). Patients were followed to earliest of index ARSI discontinuation or switch, radiopharmaceutical use, end of insurance or clinical activity, or end of data availability (30 Sep 2022). Inverse probability treatment weighting (IPTW) was used to reduce potential pre-index confounding, controlling for age, race, region, insurance payer, index year, time from metastasis to index date, time from first prostate cancer (PC) diagnosis to index date, metastasis locations, de novo PC, use of androgen deprivation therapy, first-generation antiandrogens or chemotherapy, most recent PSA and testosterone levels, and most recent Gleason score. PSA90 was defined as the earliest attainment of ≥90% decline in PSA relative to pre-index (most recent value within 13 weeks). The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: A total of 917 APA and 632 ABI patients were identified. Patient characteristics were balanced with IPTW (Table). By 6 months post-index, 80.9% of APA and 72.8% of ABI patients had a PSA measurement. By 6 months, significantly more APA patients attained a PSA90 response, as compared to ABI patients (P &lt; 0.001; Table). Median time-to-PSA90 was 3.5 months for APA patients and 8.8 months for ABI patients. Conclusions: This real-world study supports previous findings that a greater percentage of patients with mCSPC in the US initiating APA achieved deep PSA response compared to those initiating ABI. [Table: see text]

Real-world comparison of prostate-specific antigen (PSA) response in patients with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or enzalutamide (ENZ).

51 Background: APA and ENZ, two androgen receptor synthesis inhibitors (ARSIs), used in combination with androgen deprivation therapy (ADT) are among the recommended treatments for patients with mCSPC. Deep PSA response, evaluated as ≥90% PSA decline (PSA90), is an important outcome after ARSI initiation, with early, deep response associated with longer survival. The primary objective of this study was to compare PSA90 response in ARSI-naïve patients with mCSPC by 6 months after initiating APA or ENZ in real-world clinical practice. Methods: Linked electronic medical record (EMR) data of US community urology practices in the from PPS Analytics and administrative health data from Komodo Health Solutions Research Database were evaluated. Patients with mCSPC were selected into two cohorts, based on the index date, defined as the first paid pharmacy claim or in-office dispensation for APA or ENZ on or after 16 Dec 2019. Patients were required to have ≥12 months of pre-index EMR clinical activity. Pre-index characteristics (i.e., age, race, geographic region, payer type, index year, time from metastasis, time from first prostate cancer [PC] diagnosis, de novo PC, ADT use, first-generation antiandrogen use, chemotherapy use, metastasis locations, most recent PSA level, testosterone level, and Gleason score) were balanced between cohorts with inverse-probability treatment weighting (IPTW). Patients were followed from index date until the earliest of index ARSI discontinuation or switch, radiopharmaceutical initiation, end of open administrative claim or EMR clinical activity, or end of data availability (30 Sep 2022). PSA90 was defined as the earliest ≥90% decline in PSA relative to most recent pre-index PSA. The proportion of patients achieving PSA90 was compared using a weighted Kaplan-Meier analysis and the time-to-PSA90 response was compared using a weighted Cox proportional hazards model. Results: In total 860 APA and 869 ENZ patients were identified. Patient pre-index characteristics were balanced with IPTW (Table). By 6 months post-index, 80.3% of APA and 75.0% of ENZ patients had ≥1 PSA test result. By 6 months, significantly more APA patients attained a PSA90 response, as compared to ENZ patients (p=0.005; Table). The median time to PSA90 response was 3.5 months for APA and 4.9 months for ENZ. Conclusions: This US real-world study of patients with mCSPC demonstrated that treatment with APA produces a deep, early PSA response by 6 months in a greater percentage of patients than treatment with ENZ. [Table: see text]

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.

Review of Current Treatment Intensification Strategies for Prostate Cancer Patients

Prostate cancer (PCa) used to be one of the most common nondermatologic cancers in men that can be treated only with surgery. However, a revolutionary breakthrough came in the 1980s with the introduction of long-acting luteinizing hormone-releasing hormone (LHRH) agonists for the curative treatment of PCa. This paradigm shift contributed to the combined use of androgen deprivation therapy (ADT), chemotherapy, and radiotherapy for the treatment. The latest data highlight the use of treatment intensification (TI), i.e., combined use of radiotherapy (RT) and hormonal or drug treatments, for localized or locally advanced PCa. Indeed, the results of combined modality treatments have shown a reduction in disease-specific mortality and improved overall survival. Although TI seems promising, more research studies are warranted to confirm its efficacy. This review summarizes the latest available outcome results of pivotal trials and clinical studies on the efficacy of TI.

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.

Abstract 14846: Rurality and Associated Cardiovascular Events and Mortality in Older Men With Prostate Cancer: Longitudinal SEER Medicare Analysis

Introduction: The effect of rurality as a social determinant of health in cardiovascular events (CVE) in patients with prostate cancer (PC) is unknown. Methods: Using the Surveillance, Epidemiology, and End Results-Medicare linked database, we identified males ≥ 66 years old with a new primary diagnosis of PC between 2009 and 2017. We also identified those who were undergoing leuprolide androgen deprivation therapy (ADT). These patients were followed to identify a primary outcome of CVE that included heart failure (HF), atrial fibrillation (AF), acute myocardial infarction (AMI), peripheral artery disease (PAD), coronary artery disease (CAD), ischemic stroke (IS) and cardiovascular death. Adjusted Cox proportional hazards modeling was performed to estimate all-cause mortality in PC patients stratified by rurality as defined by Medicare. Adjusted Fine-Gray modeling with appropriate competing risk (mortality or type of mortality) was utilized for other outcomes as presented. We adjusted for demographic factors, social determinants of health, cancer-specific factors, and other cardiovascular risk factors apart from the primary exposure of rurality. Results: This study included 102,225 PC patients. Among these, 4,945 (4.8%) belonged to areas with a population of less than 2,500 or less than 20,000 not next to a metro (rural). The use of ADT was noted in 9,071 (8.9%) of patients. The incidence of new CVE and mortality risk due to rurality is presented in Table 1. Rural area was noted to be a risk factor for all-cause mortality [adjusted hazards ratio (aHR) = 1.114 (95% CI= 1.070-1.161)]. No statistically significant association between CVE and rurality, however, was observed in the data. Conclusions: PC patients have a high burden of pre-existing cardiovascular disease prior to PC diagnosis, and rurality increases all-cause mortality. This is consistent with those who are treated with ADT as well.

Impact of the COVID-19 pandemic on delivery of prostate cancer care in Australia: An interrupted time series analysis.

The COVID-19 pandemic led to a major disruption to health services across the world. The aim of this population-based study was to assess the downstream effects of the pandemic on diagnostic tests and treatment activities related to prostate cancer (PC). The Australian Government Department of Health Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme databases were queried from January 2010 to June 2022. Two interrupted time series were performed Pre-COVID (January 2010 to February 2020) and peri-COVID (March 2020 to June 2022). Temporal modeling was performed to account for seasonal variation. Pre-COVID-19, monthly prostate-specific antigen (PSA) testing showed a declining trend and testing decreased by 81 tests per 100 000 annually. A single-month 38% drop in PSA testing was observed in April 2020; this corresponded to Australia's first wave. No change was observed in the rate of prostate biopsies. Peri-COVID-19 outbreaks, there was a slight shift toward the use of long-acting androgen deprivation therapy (ADT) at 4% with a predilection still for short-acting agents. with no registered change in the overall volume of radiotherapy or surgery. There were no deficits in the number of diagnostic and treatment activities for men with PC. Aside from a slight shift toward long-acting ADT use during the pandemic, no other patterns were observed. The longer-term impact such as missed diagnosis or late presentation affecting chances of survival due to COVID-19 is yet to be ascertained.

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.

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.

Radiation-Associated Lymphopenia in Advanced Prostate Cancer Treated with Contemporary Radiation Techniques.

Lymphocytes play a critical role in the immune system as primary effector cells for cancer control, often depleted by external beam radiation therapy (EBRT). Radiation-associated lymphopenia (RAL) has been shown to be a poor prognostic factor in the management of multiple solid tumors. We hypothesize RAL is similarly observed in advanced prostate cancer (PC) RT with contemporary techniques. We identified patients with advanced PC (high-risk or clinical/pathologic node-positive) receiving EBRT including lymph node/prostatic lesion boost on a prospective collection protocol for whom 1 baseline and ≥2 subsequent complete blood count (CBC) with differential samples were available, collected at RT end, 3-, 6-, and 12-months post-RT. Clinicopathological characteristics were retrieved from chart review. Common Terminology Criteria for Adverse Events (CTCAE)v5 was used to grade absolute lymphocyte count (ALC); RAL was defined as CTCAEv5 grade ≥2. As these patients received pelvic nodal irradiation, they were pooled with low/intermediate-risk PC cohort treated with high dose-rate (HDR) brachytherapy or prostate alone EBRT with similar CBC timepoints for univariable analysis to understand RT field size effect on RAL. Between 2019 and 2022, among 17 patients in the low/intermediate-risk PC cohort, 6 patients had grade ≥2 lymphopenia. Among 25 patients in the advanced PC cohort, all received androgen deprivation therapy (ADT), 6 received lymph node boost, and 5 received prostatic lesion boost. At RT end, leukopenia was prominently observed (median nadir count 75.1% of baseline), with ALC as major driver (median nadir count 27.3% of baseline). Grade ≥2 lymphopenia was observed in 76% of patients (n = 19) Of 19 advanced PC patients who reached 6 months post-RT follow-up, median ALC was 53.0% of baseline, and Grade ≥2 lymphopenia remained in 37% (n = 7) of patients. Of 8 advanced PC patients who reached 12 months post-RT follow-up, median ALC was 55.6% of baseline. When evaluating whether RT dose or field size contributed to lower nadir ALC counts, combining the low/intermediate-risk and advanced PC cohorts (n = 42), univariable analysis demonstrated Gleason grade group (p = 0.009), RT field size (p = 0.020), ADT use (p = 0.020), baseline ALC (p = 0.037), and baseline hemoglobin (p = 0.009) were independent predictors of Grade ≥2 lymphopenia. Age, prostatic lesion/lymph node boost, and equivalent dose in 2 Gy/fraction (EQD2) were nonsignificant. Grade ≥2 RAL was observed in patients with advanced PC at end of RT, irrespective of age, RT boost, or EQD2. Lymphocyte recovery from baseline can be prolonged even at 12 months post-RT. Ongoing analyses include expanding data with additional serial CBC, increasing cohort size, and integrating effect of additional systemic therapies. RAL has downstream implications for future chemotherapy/radiopharmaceuticals.

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.