Long-term Androgen Deprivation Therapy Research Articles

MP79-16 LONG-TERM RESULTS OF CYTOREDUCTIVE RADICAL PROSTATECTOMY IN MEN WITH HORMONE-NAIVE, LOW VOLUME METASTATIC PROSTATE CANCER(MHNPCA)

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) IV (MP79)1 Apr 2020MP79-16 LONG-TERM RESULTS OF CYTOREDUCTIVE RADICAL PROSTATECTOMY IN MEN WITH HORMONE-NAIVE, LOW VOLUME METASTATIC PROSTATE CANCER(MHNPCA) Patricia John*, David Pfister, Axel Heidenreich, and Florian Hartmann Patricia John*Patricia John* More articles by this author , David PfisterDavid Pfister More articles by this author , Axel HeidenreichAxel Heidenreich More articles by this author , and Florian HartmannFlorian Hartmann More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000971.016AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Androgen deprivation combined with apalutamide, abiraterone or docetexal represents the treatment of choice in mhnPCA. Cytoreductive radical prostatectomy (cRP) has been proposed as part of a multimodality treatment in selected patients with oligometastatic prostate cancer. Recently, our group has demonstrated that the combination of 6 months neoadjuvant ADT followed by cRP exerted a significant benefit in terms of progression-free, local symptom-free survival and time to castration resistance. We report on the long-term outcome of this cohort of men with low volume mhnPCA. METHODS: 32 patients with hnmPCA were retrospectively analysed. All men had low volume skeletal metastases (≤3 lesions on a bone scan), absence of visceral and retroperitoneal lymph node metastases, and a PSA-decrease <1,0 ng/ml following 6 months of ADT. 38 case-matched patients with mhnPCA and ADT monotherapy served as a control group. Perioperative complications were assessed according to Clavien-Dindo, PSA-free, symptom-free, cancer specific and overall survival was analysed and assessed via descriptive statistics. RESULTS: Mean age of the patients was 61 (42–69) years. Mean PSA at time of diagnosis was 135.2 (3.5-150.4) ng/ml, the mean PSA at time of cRP was 0.42 (0.01-9.8) ng/ml. All patients demonstrated a mean of 2.1 (1-3) osseous metastases, intrapelvic lymph node metastases were identified preoperatively in 17.4% of patients. All men underwent cRP and extended pelvic lymphadenectomy. The median follow-up is 75,5 (7–135) months, 27/32 (84.4%) patients are still alive. 16/27 (59.2%) have developed mCRPC. Median overall survival is 78.9 months and the median time to CRPC is 40 (9–65) months. Overall survival, progression-free survival and time to CRPC was significantly superior in the cRP group as compared to ADT alone (p = 0.003). 10 (31.2%) patients developed perioperative complications of whom only 3/32 (9.4%) patients required interventions and were defined as Clavien-Dindo IIIa/b. 28/32 (87.5%) patients are continent (0-1 pads/day). None of the patients developed locally symptomatic relapses after cRP whereas this was the case in 12 (31.6%) pts in the ADT alone group. CONCLUSIONS: Even after long-term follow-up neoadjuvant ADT and cRP result in good oncological and functional outcome with a 6-year overall survival rate of more than 80%. As compared to about 25% symptomatic local relapses following radiation therapy and to 31% relapses following ADT alone, none of the patients developed symptomatic local relapses following cRP. Although data from prospective randomized trials are lacking, cRP should be considered as a valid treatment option in well selected patients with low volume metastatic disease and good response to neoadjuvant ADT. Source of Funding: None © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e1221-e1222 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Patricia John* More articles by this author David Pfister More articles by this author Axel Heidenreich More articles by this author Florian Hartmann More articles by this author Expand All Advertisement PDF downloadLoading ...

Combined Long-Term Androgen Deprivation and Pelvic Radiotherapy in the Post-operative Management of Pathologically Defined High-Risk Prostate Cancer Patients: Results of the Prospective Phase II McGill 0913 Study.

Purpose: Following radical prostatectomy, prostate bed radiotherapy (PBRT) has been combined with either long-term androgen deprivation therapy (LT-ADT) or short-term ADT with pelvic lymph node radiotherapy (PLNRT) to provide an oncological benefit in randomized trials. McGill 0913 was designed to characterize the efficacy of combining PBRT, PLNRT, and LT-ADT. It is the first study to do so prospectively.Methods: In a single arm phase II trial conduced from 2010 to 2016, 46 post-prostatectomy prostate cancer patients at a high-risk for relapse (pathological Gleason 8+ or T3) were assessed for treatment with combined LT-ADT (24 months), PBRT, and PLNRT. Patients received PLNRT and PBRT (44 Gy in 22 fractions) followed by a PBRT boost (22 Gy in 11 fractions). The primary endpoint was progression-free survival (PFS). Toxicity and quality of life (QoL) were evaluated using CTCAE V3.0 and EQ-5D-3L questionnaires, respectively.Results: Among the 43 patients were treated as per protocol, median PSA was 0.30 μg/L. On surgical pathology, 51% had positive margins, 40% had Gleason 8+ disease, 42% had seminal vesicle involvement, and 19% had lymph node involvement. At a median follow-up of 5.2 years, there were no deaths or clinical progression. At 5 years, PFS was 78.0% (95% Confidence Interval 63.7–95.5%). Not including erectile dysfunction, patients experienced: 14% grade 2 endocrine toxicity while on ADT, one incident of long-term gynecomastia, 5% grade 2 acute urinary toxicity, 5% grade 2 late Urinary toxicity, and 24% long-term hypogonadism. No comparison between the average or minimum self-reported QoL at baseline, during ADT, nor after ADT demonstrated a statistically significant difference.Conclusions: Combining PBRT, PLNRT, and LT-ADT had an acceptable PFS in patients with significant post-operative risk factors for recurrence. While therapy was well-tolerated, long-term hypogonadism was a substantial risk. Further investigations are needed to determine if this combination is beneficial.Trial registration: NCT01255891.

Association of black race with improved outcomes following definitive radiotherapy with androgen deprivation therapy for high-risk prostate cancer: A meta-analysis of eight randomized trials.

327 Background: Though Black men with prostate cancer are more likely to have aggressive disease features than White men, race-specific differences in initial treatment responses in localized disease remains unknown. Methods: Individual patient data were obtained for 9259 patients (including 1674 [18.1%] Black men and 7585 [81.9%] White men) enrolled on eight randomized controlled trials evaluating definitive radiotherapy (RT) ± short-term or long-term androgen deprivation therapy (STADT and LTADT). The primary endpoints were biochemical recurrence (BCR), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Fine-Gray subdistribution HR (sHR) models were developed to evaluate the cumulative incidences of all endpoints after stratification by National Comprehensive Cancer Network risk grouping. A meta-analysis was done to estimate pair-wise comparisons of treatments within and between Black and White men, after adjusting for age, Gleason score, clinical T stage, and initial PSA. Results: Black men were more likely to have NCCN high-risk disease at enrollment (656/1674 [39.2%] vs 2506/7585 [33%], p&lt;0.001). However, within the high-risk stratum Black men had lower 10-year rates of BCR (46.1% vs. 50.4%, p=0.02), DM (14% vs. 21.6%, p&lt;0.001), and PCSM (4.9% vs. 9.8%, p&lt;0.001). After adjusting for age and disease characteristics, Black men with high-risk prostate receiving RT+STADT had lower rates of BCR (sHR 0.73, 95% CI 0.62-0.86, p&lt;0.001), DM (sHR 0.64, 95% CI 0.49-0.84, p=0.001) and PCSM (sHR 0.49, 95% CI 0.25-0.95, p=0.04). There were no differences in BCR, DM, or PCSM among men receiving RT+LTADT. The interaction between race and the impact of adding STADT to RT alone on BCR was statistically significant (p=0.003). Conclusions: Black men enrolled on randomized trials with long-term follow-up have higher risk disease at enrollment, but have better BCR, DM, and PCSM outcomes with RT-based therapy compared with White men, particularly with the addition of STADT.

Testosterone recovery as biomarker for overall and cause-specific survival in combined treated patients with high-risk and locally advanced prostate cancer.

188 Background: Androgen deprivation therapy (ADT) can cause considerable toxicity and may influence outcome. The study assessed the impact of testosterone recovery (TR) on survival after ADT and definitive radiotherapy in two independent cohorts. Methods: Two hundred and forty-four patients (high risk JHH cohort N=106, T1c-T3N0M0 [A], locally advanced OUH cohort N=138, T1c-T4N0-1M0 [B]) with adenocarcinoma of the prostate were included in this retrospective analysis. Short and long-term ADT was given (median 12 months A, 24 months B, respectively,) and along with conformal external beam radiation 76-80 Gy given to the prostate in cohort A, 74 Gy prescribed in cohort B and 46-50 Gy to the whole pelvis. Testosterone levels were measured at the end of ADT and at biochemical relapse. TR was defined as ≥ 9 nmol/L. Kaplan Meier plots were generated for overall survival (OS) and cause-specific survival (CSS) stratified by TR, in addition to patient characteristics median time to TR and FU were calculated. Results: The median age in the A cohort was 66.7 years and 64.7 years in the B group. FU was 6 years for A and 8 years in B. Patients in group A received median ADT of 12 months and 24 months in group B. The median time to TR was 1.6 yr in A and 2.5 yrs in B, respectively. Patients in group A stratified to TR showed no difference in overall survival (p=0.92)), on contrary, patients in group B showed improved overall survival depending on TR (Fig. 1, KM plot, 10 year OS 75.3% vs 59.9% p=0.034). CSS was seemed to trend towards improvement with TR for cohort A (p=0.19) and was improved in cohort B (p=0.022). The Univariate ADT length, age, and RT dose was associated with time to TR, but on multivariate analysis only longer ADT time (p = 0.03) was significantly associated with time to TR. Conclusions: TR was associated with improved OS in patients with unfavorable locally advanced disease a finding not seen in patients with high-risk disease.

Navigating systemic therapy for metastatic castration-naïve prostate cancer.

The last decade has seen a remarkable shift in the treatment landscape of advanced prostate cancer, none more so than in the management of metastatic castration-naïve disease. This narrative review will examine existing and emerging evidence supporting systemic therapy use for metastatic castration-naïve prostate cancer (mCNPC) and provide guidance on the selection of these agents with respect to optimising patient outcomes. The addition of either docetaxel (chemohormonal approach) or an AR pathway inhibitor (abiraterone, enzalutamide or apalutamide) is a reasonable standard of care option for men commencing long-term ADT for mCNPC. While the issue of disease volume as a predictive biomarker for docetaxel benefit has previously been debated, recent data support consideration of upfront docetaxel in all patients, regardless of metastatic burden. Decisions regarding systemic treatment for men with mCNPC should be based on comprehensive consideration of disease, patient and logistical factors. Multiple novel therapeutics for mCNPC are currently under active investigation. The introduction of potent systemic therapy earlier in the mCNPC disease course has resulted in dramatic improvements in clinical outcomes for patients. As the management of mCNPC continues to evolve, the future remains promising, with the expectation of ongoing improvements to patient outcomes and quality of life.

Impact of Lifestyle Intervention for Patients with Prostate Cancer.

Objectives: Androgen-deprivation therapy (ADT) for prostate cancer (PCa) is associated with reduced physical function and quality of life (QoL). We investigated the impact of a structured lifestyle intervention on the promotion of physical activity (PA) and reduction of sedentary behavior (SB), and its effect on QoL in men on ADT. Methods: Patients with advanced PCa on long-term ADT were randomized to the intervention (N = 11) or a control arm (N = 10) between February 2018 and May 2019. The intervention group received a structured lifestyle intervention including motivational text messages for 8 weeks (maintenance visit at week 12). At each visit, self-report measures and accelerometer data were used to assess PA and SB, and questionnaires were used to measure QoL, life satisfaction, anxiety, and depression. Results: Significantly greater improvements in QoL and depression compared to baseline were reported in the intervention group compared to the control group. In addition, the intervention group also showed a significantly greater increase in self-reported light, as well as moderate-to-vigorous PA, and reduction in self-reported SB. Conclusions: Given its inherent advantage in improving QoL and reducing depression, a lifestyle intervention program should be offered to patients on ADT.

How Does Androgen Deprivation Therapy Affect Mental Health including Cognitive Dysfunction in Patients with Prostate Cancer?

Androgen deprivation therapy (ADT) is used to block the release of androgen in prostate cancer to promote the regression of cancer cells, and hence, disease progression. Its indication has been widened from the metastatic setting to the localized setting in prostate cancer. Long-term ADT for suppressing androgen release leads to a rapid decrease in androgen, termed as andropause, resulting in several dose and duration dependent adverse effects, including cognitive dysfunction such as dementia. Many retrospective and prospective studies, as well as meta-analyses, have attempted to confirm the crucial relationship between ADT and cognitive dysfunction, but pro and contrary opinions regarding this issue are ongoing owing to the absence of randomized controlled trials. Additionally, several recent studies have suggested the negative effects of dose- and duration-dependent ADT on cognitive dysfunction, especially in 40–65-year-old patients with prostate cancer, who are currently active workers in the society. This review article discusses several studies examining the influence of ADT on mental health based on diverse significant perspectives, especially cognitive dysfunction.

Hyprofractionated Versus Conventionally Fractionated Radiation Therapy for Patients with Intermediate- or High-Risk, Localized, Prostate Cancer: 7-Year Outcomes From the Randomized, Multicenter, Open-Label, Phase 3 HYPRO Trial

In the multicenter, phase 3, HYpofractionated irradiation for PROstate cancer trial, hypofractionated (HF) radiation therapy was compared with conventionally fractionated (CF) radiation therapy. In previous reports, we could not demonstrate the postulated superiority of hypofractionation in terms of relapse-free survival at 5 years. The frequent use of long-term androgen deprivation therapy might have had substantial effects on relapse-free survival. In the current analysis, we provide updated 7-year relapse-free survival outcomes. We enrolled patients with intermediate- to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer. Patients were randomly assigned (1:1) to either HF (64.6 Gy in 19 fractions) or CF (78.0 Gy in 39 fractions) radiation therapy. Based on an estimated α/β ratio for prostate cancer of 1.5 Gy, the EQD2 was 90.4 Gy for HF versus 78.0 Gy for CF radiation therapy. The primary endpoint of the present analysis is relapse-free survival at 7 years. A total of 820 patients were enrolled, of whom 804 were assessable for the current evaluation (407 HF versus 397 CF). Median follow-up was 89 months (interquartile range, 83-99). Concomitant androgen deprivation therapy was prescribed for 537 (67%) of 804 patients for a median duration of 32 months (interquartile range, 10-44). Treatment failure at 7 years was reported in 220 (27.4%) of 804 patients, 107 (26.3%) in HF versus 113 (28.5%) in CF radiation therapy. Seven-year relapse-free survival was 71.7% (95% confidence interval [CI], 66.4-76.4) for HF versus 67.6% (95% CI, 62.0-72.5) for CF (P = .52). Overall survival was 80.8% (95% CI, 76.5-84.4) in HF versus 77.6% (95% CI, 73.0-81.5) in CF radiation therapy (P = .17). The current results of 7-year relapse-free survival confirmed our previous findings that the hypothesized dose escalation in the HF arm did not translate to superior tumor control compared with the CF arm.

883P - Androgen receptor (AR) aberrations in patients (Pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN

883P - Androgen receptor (AR) aberrations in patients (Pts) with metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) plus androgen deprivation therapy (ADT) in TITAN

855PD - Docetaxel for hormone-naïve prostate cancer (PCa): Results from long-term follow-up of non-metastatic (M0) patients in the STAMPEDE randomised trial

855PD - Docetaxel for hormone-naïve prostate cancer (PCa): Results from long-term follow-up of non-metastatic (M0) patients in the STAMPEDE randomised trial

Combining prostate cancer radiotherapy with therapies targeting the androgen receptor axis.

Prostate cancer (pca) is the most common non-dermatologic cancer and the 3rd leading cause of male cancer mortality in Canada. In patients with high-risk localized or recurrent pca, management typically includes the combination of long-term androgen deprivation therapy (adt) and radiotherapy (rt). New androgen-receptor-axis targeted therapies (arats), which await validation, offer an option to intensify therapy. In this narrative review, we report the relevant history that has supported combining adt with rt. The literature in PubMed was searched for studies involving pca and novel arats (abiraterone acetate, enzalutamide, apalutamide, darolutamide) published between 1995 and 2019. Literature discussing clinical trials in which those modalities were combined was extracted and synthesized into a combined molecular and clinical discussion. Potential treatment intensification mechanisms and rationales are explored. Early results from three phase i/ii trials demonstrated that concurrent abiraterone acetate, adt, and rt is safe, improves the extent of chemical castration, and is associated with limited treatment failures. A single in vitro study implies synergy for radiosensitization beyond that facilitated by conventional adt. Studies investigating the combination of other arats with rt are under way, including multiple phase iii trials, but short-term results are not yet available.

844O - Docetaxel for hormone-naïve prostate cancer: Results from long-term follow-up of metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476) and sub-group analysis by metastatic burden

844O - Docetaxel for hormone-naïve prostate cancer: Results from long-term follow-up of metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476) and sub-group analysis by metastatic burden

867P - Multi-institutional evaluation of therapeutic management for oligometastatic cancer prostate recurrence with choline-PET/CT

BackgroundCholine Positron Emission Tomography – Computed Tomography (Choline PET/CT) allows for the diagnosis of oligometastatic (OM) Prostate Cancer (PCa) recurrence that could be treated with a curative intent. The aim of the study was to evaluate the different therapeutic approaches and outcomes for first OM recurrence. MethodsThis multi-institutional, retrospective study included patients with a hormone-sensitive biochemical PCa recurrence after an initial curative local treatment, and with at least 1 to 5 Choline PET/CT-diagnosed metastatic lesions. Primary endpoint was Biochemical Recurrence Free Survival (BRFS). Secondary endpoints were Metastatic Recurrence-Free Survival (MRFS) and Androgen Deprivation Therapy-Free Survival (ADT-FS). ResultsBetween October 2012 and December 2016, 177 patients were included. Sixty-eight patients (38.4%) received an ADT alone, 72 (40.7%) received an External Beam Radiation Therapy (EBRT) – ADT association, 28 (15.8%) received an EBRT, 6 (3.4%) received a surgery, and 2 (1.1%) received a surgery with ADT. Median follow-up was 49 months [95%CI, 44.3-53.4]. Among patients who received non-standard treatment, 55% avoided long-term ADT. Grade 3 acute and late toxicities were rare (0.8% and 2.5% respectively). The median BRFS, MRFS and ADT-FS were 42 [95%CI, 37-51], 61 [95%CI, 45-81], and 53 [95%CI, 45-60] months, respectively. In multivariate analysis, concomitant ADT with MDT and "regional" EBRT combined with MDT significantly improved BRFS (p<0.0001 and p=0.0113 respectively) and MRFS (p=0.0005 and p=0.0013 respectively). In multivariate analysis, a PSA-doubling time of>3 months had a statistically significant positive impact on MRFS (p=0.0496) and ADT-FS (p=0.0007). The overall and disease specific survivals were 87% and 97% respectively at 5 years. The median incidence of castration resistant PCa was 80 months. ConclusionsIn patients with hormone-sensitive OM PCa recurrence after initial local treatment, BRFS and MRFS were significantly improved when concomitant ADT and "regional" EBRT were combined with MDT. Clinical trial identificationOMPPC-IPC 2018-059. Legal entity responsible for the studyInstitute Paoli-Calmettes. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BackgroundSTAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients.MethodsWe randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional.ResultsBetween 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69–0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57–0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59–0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression).ConclusionsThe clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Plasma Androgen Receptor Copy Number Status at Emergence of Metastatic Castration-Resistant Prostate Cancer: A Pooled Multicohort Analysis.

Increases in androgen receptor (AR) copy number (CN) can be detected in plasma DNA when patients develop metastatic castration-resistant prostate cancer. We aim to evaluate the association between AR CN as a continuous variable and clinical outcome. PCR2023 was an international, multi-institution, open-label, phase II study of abiraterone acetate plus prednisolone (AAP) or abiraterone acetate plus dexamethasone that included plasma AR assessment as a predefined exploratory secondary end point. Plasma AR CN data (ClinicalTrials.gov identifier: NCT01867710) from this study (n = 133) were pooled with data from the following three other cohorts: cohort A, which was treated with either AAP or enzalutamide (n = 73); the PREMIERE trial (ClinicalTrials.gov identifier: NCT02288936) of biomarkers for enzalutamide (n = 94); and a phase II trial from British Columbia (ClinicalTrials.gov identifier: NCT02125357) that randomly assigned men to either AAP or enzalutamide (n = 201). The primary outcome measures for the biomarker analysis were overall survival and progression-free survival. Using multivariable fractional polynomials analysis using Cox regression models, a nonlinear relationship between plasma AR CN and outcome was identified for overall survival, where initially for small incremental gains in CN there was a large added hazard ratio that plateaued at higher CN. The CN cut point associated with the highest local hazard ratio was 1.92. A similar nonlinear association was observed with progression-free survival. In an exploratory analysis of PCR2023, the time from start of long-term androgen-deprivation therapy to start of AAP or abiraterone acetate plus dexamethasone was significantly shorter in patients with plasma AR CN of 1.92 or greater than patients with plasma AR CN of less than 1.92 (43 v 130 weeks, respectively; P = .005). This was confirmed in cohort A (P = .003), the PREMIERE cohort (P = .03), and the British Colombia cohort (P = .003). Patients with metastatic castration-resistant prostate cancer can be dichotomized by a plasma AR CN cut point of 1.92. Plasma AR CN value of 1.92 or greater identifies aggressive disease that is poorly responsive to AR targeting and is associated with a prior short response to primary androgen-deprivation therapy.

Contemporary analysis of bone mineral density in men initiating androgen deprivation therapy for prostate cancer.

38 Background: Androgen deprivation therapy (ADT) is a cornerstone of advanced prostate cancer (PCa) treatment, however several side-effects are associated with its long-term use. Notably, loss of bone mineral density (BMD) is accelerated which increases fracture risk. Guidelines recommend BMD testing when initiating ADT to properly assess baseline fracture risk. The objective was to examine the proportion of BMD testing in men initiating long-term ADT in Quebec. Methods: The cohort consists of men extracted from Quebec public healthcare insurance administrative databases who were diagnosed with PCa from 2001-2012 and treated by ADT for at least one continuous year. The primary study outcome was the receipt of baseline BMD testing (defined as a BMD test identified in the period from 6 months prior to and up to 12 months after ADT initiation). Multivariable generalized linear mixed with a logit link was performed to identify variables associated with baseline BMD testing accounting for physician clustering. Results: We identified 7,069 patients, of which 887 (12.6%) underwent baseline BMD testing. Baseline BMD testing varied by year of ADT initiation, from 7.7% in 2001-2003 to 12.3% in 2013-2012. Following multivariable analyses, later years of ADT initiation (2004-2006, 2007-2009, 2010-2012, 2013-2015) remained associated with higher odds of baseline BMD testing compared to the earlier years (2001-2003) (ORs ranging from 1.43-1.88; p &lt; 0.001). Conversely, age &gt; 80 (OR 0.73; 95% CI 0.57-0.94; p = 0.001), greater Charlson comorbidity score (OR 0.51; 95%CI 0.34-0.75; p = 0.001), and rural residence (OR 0.60; 95%CI 0.48-0.75; p &lt; 0.001) were associated with lower odds of baseline BMD testing. Conclusions: In our study population, rates of baseline BMD testing in men initiating ADT are low, although the rates increased over the course of the study period. Potential gaps identified in baseline BMD testing include older, more comorbid patients, and rural residence. Additional efforts emphasizing the importance of BMD testing in PCa guidelines may be needed.

Gleason pattern 5 is associated with an increased risk for metastasis following androgen deprivation therapy and radiation: An analysis of RTOG 9202 and 9902

Background/purposeStratification of Gleason score (GS) into three categories (2–6, 7, and 8–10) may not fully utilize its prognostic discrimination, with Gleason pattern 5 (GP5) previously identified as an independent adverse factor. Materials/methodsPatients treated on RTOG 9202 (n = 1292) or RTOG 9902 (n = 378) were pooled and assessed for association of GS and GP5 on biochemical failure (BF), local failure (LF), distant metastasis (DM), and overall survival (OS). Fine and Gray’s regression and cumulative incidence methods were used for univariate and multivariate analyses. ResultsWith median follow-up of 9.4 years, patients with GS 8–10 with GP5 had worse outcome than GS 4 + 4 for DM on both RTOG9202 (p = 0.038) and RTOG9902 (p < 0.001) with a trend toward worse OS (p = 0.059 and p = 0.089, respectively), but without differences in BF or LF. At 10-years DM was higher by 11% (RTOG 9202) and 18% (RTOG 9902) with GP5 compared to GS 4 + 4. On multivariate analysis restricted to long-term androgen deprivation therapy the presence of GP5 substantially increased distant metastasis (HR = 0.43, 95%CI: 0.24–0.76, p = 0.0039) with a trend toward worse OS (HR:0.74, 95% CI:0.54–1.0, p = 0.052) without association with LF (HR:0.55, 95%CI:0.28–1.09, p = 0.085) or BF (HR:1.15, 95%CI:0.84–1.59, p = 0.39). We did not observed substantial differences between Gleason 3 + 5, 5 + 3, or Gleason 9–10. ConclusionsThese results validate GP5 as an independent prognostic factor which is strongest for DM. As a result GP5 should be considered when stratifying patients with GS 8 and may be a patient population in which to evaluate newly approved systemic therapies or additional local treatments.

Bone Mineral Density Changes in Patients with Prostate Cancer Treated with Androgen Deprivation Therapy and External Beam Radiation Therapy: Hip and Spine Comparison

Use of androgen-deprivation therapy (ADT) in high risk prostate cancer (PrCa) improves disease outcomes but decreases bone mineral density (BMD). External beam radiation therapy (RT) has been implicated in bone loss and skeletal events in the hip/pelvis. Little is known about differential BMD changes in skeletal sites over time in men with PrCa treated with long term ADT (LT-ADT) and RT. We hypothesized that there would be a greater decrease in BMD in the hip (RT exposed) than spine (not RT exposed). A retrospective review of men with PrCa treated with LT-ADT and definitive RT was conducted to evaluate BMD changes in the hip and spine. Patients treated from 2004 to 2017 were included if they received >1yr of ADT, pelvic RT as a component of treatment, and had baseline and follow up dual-energy X-ray absorptiometry (DXA) scan(s). ADT included total androgen blockade pre/during RT followed by LHRH agonist alone. Longitudinal comparisons of BMD changes between femoral neck (FN), total hip (TH) and lumbar spine (SP) from start of ADT were performed. Bone loss on DXA was managed as clinically indicated by T-score criteria (normal, osteopenia, osteoporosis). BMD decreases of ≥0.03 g/cm2 and change in T-score criteria were considered significant. FN and TH were contoured on and dosimetry collected from RT plans. A T-test was used to compare changes between sites (with a significance level of p<0.05). The 50 patients included for analysis had a median age of 68 yrs (43-82); duration of ADT of 27.8 mos (14.6-51.3); and follow up of 4.6 yrs (1.7-14.7). Mean doses from RT plans were: right FN 21.9 Gy (9.7-40.3) and TH 20.6 Gy (11.3-34.4), left FN 21.8 Gy (1-34.4) and TH 21.6 Gy (12.6-60.1). DXA scans at yearly timepoints (+/-6mos) were reviewed: n=35 at 1 yr, n=25 at 2 yrs, and n=11 at 3 yrs. Mean BMD declines (g/cm2) at FN, TH, and SP were: -0.026 (2.9%), -0.015 (1.4%), and -0.029 (2.3%) at 1 yr; -0.026 (2.7%), -0.045 (4.2%), and -0.027 (2%) at 2 yrs; and -0.042 (4.1%), -0.047 (4.4%), and -0.096 (7.6%) at 3 yrs. Comparisons of absolute and % BMD changes showed no significant difference in bone loss in FN vs SP or TH vs SP (all p values>0.05). In subsets with decrease in BMD at any site of ≥0.03 g/cm2, there remained no pattern of greater bone loss in FN vs SP (n=45) or TH vs SP (n=48). 21 declines in T-score criteria were observed, more often in spine than hip (9 SP, 6 FN, 6 TH). Of the 9 SP, 5 declined in SP only; and 3 FN and 2 TH declined without change in SP. Pelvic RT + LT-ADT for advanced PrCa was not associated with greater BMD decrease in the FN/TH (RT exposed) versus lumbar SP (not RT exposed). These preliminary results challenge the notion that the primary influence of bone loss and potential skeletal events in patients treated with RT + LT-ADT is due to the contributions of RT when LT-ADT is used; and should be verified prospectively.

Stereotactic Ablative Radiotherapy (SABR) May Reduce the Need for Long-Term Androgen Deprivation Therapy (ADT) in Patients with Oligometastatic Prostate Cancer

We hypothesized that using SABR to treat men with 1-5 prostate adenocarcinoma metastases may reduce the need for long-term ADT. Men with 1-5 nodal, skeletal, or visceral prostate adenocarcinoma metastases were treated with SABR on a prospective clinical trial (NCT01859221) or registry. Active prostate disease was treated with standard radiotherapy. ADT was recommended but not required. Follow-up imaging was not required without PSA progression. Biochemical progression-free survival (bPFS) was defined as a PSA rise ≥2 ng/mL after SABR, clinical-PFS (cPFS) as new metastases on radiographic/clinical assessment, castrate-resistant-PFS (CRPC-PFS) as PSA/clinical progression despite continuous ADT, and widespread progression-PFS as ≥6 new metastases. Outcomes were assessed using the Kaplan Meier method from the start of the first course of SABR. Additional courses of SABR were considered at the time of oligoprogression. Metastasis site control was calculated from the start date of each course of SABR and censored at time of last imaging/biochemical assessment or widespread progression. Univariate analysis was performed using log-rank test. 37 men (29 clinical trial and 8 prospective registry) received SABR to 102 metastases (62 non-spine bone, 22 spine, 17 lymph node, and 1 lung). 95% had hormone sensitive disease. Doses ranged from 18-50 Gy in 1-10 fractions (50 Gy/10, 64% and 50Gy/5, 30%). 6 patients had synchronous primary disease. 32% had 1 metastasis, 32% had 2 metastases, and 34% had 3-5 metastases. 9 patients (24%) declined ADT, 15 (41%) stopped ADT after 6-12 months, and 13 (35%) remained on long-term continuous or intermittent ADT (≥24 months). Median follow-up was 3.6 years (1.7-5.2 years). 3-year metastasis site control was 97%. There was a trend towards improved 3-year bPFS survival in men who received upfront long-term ADT compared with no/short-term ADT (51% versus 14%, p = 0.08). However, long-term ADT did not appear to improve OS (80% versus 86%, p = 0.33), CRPC-PFS (61% versus 78%, p = 0.5), widespread-PFS (51% versus 61%, p = 0.74), or cPFS (38% versus 41%, p = 0.86). Of the 24 patients who initially declined or received short-term ADT, the median time to next therapy was 1.8 years (0.6-5.2), and 63% remain alive without clinical or 46% without biochemical progression and 21% remain off therapy. Only 1 grade 3+ toxicity (lumbar radiculopathy) was attributed to SABR. Oligometastatic prostate cancer caries a favorable long-term prognosis and SABR resulted in excellent metastasis site control with low morbidity. The majority of men declined upfront long-term ADT with no apparent impact on clinical disease control, progression to CRPC, or survival. These results warrant further validation including assessment on the impact on quality of life.

KAT5 Negatively regulates the proliferation of prostate cancer LNCaP cells via the caspase 3-dependent apoptosis pathway

ABSTRACTProstate cancer is one of the most common cancers in men over the age of sixty. Lysine acetyltransferase 5 (KAT5) is a histone acetyltransferase involved in transcriptional regulation, DNA repair, and cell signaling pathways. Previous studies have shown that KAT5 expression is reduced in the cytoplasm of the prostate cancer cell line LNCaP when exposed to androgen. Moreover, KAT5 has been reported to have a role in the molecular pathway leading to androgen-independent prostate cancer after long-term androgen deprivation therapy. Here, we showed that KAT5 expression was significantly reduced in prostate cancer tissues and cell lines by using the public databases Oncomine and Human Protein Atlas. Reduced KAT5 expression was significantly associated with high mortality in prostate cancer patients. Furthermore, KAT5 overexpression increased the level of apoptotic markers, such as cleaved-caspase 3, in LNCaP cells, thus enhancing the apoptotic death of LNCaP cells. Taken together, KAT5 induced apoptosis in prostate cancer cells via the caspase-3 pathway, indicating that KAT5 could be a gene therapy target for prostate cancer.