Long-term Androgen Deprivation Research Articles

Health professionals' views on discontinuation of long-term antidepressants: a systematic review and thematic synthesis.

Long-term antidepressant use, much longer than recommended by guidelines, may cause harmful effects and generate unnecessary costs. To investigate health professionals (HPs) views of long-term antidepressant discontinuation and their barriers and facilitators. Systematic review and meta-synthesis. We included studies that used qualitative data collection and had data on HPs perceptions on (dis)continuing AD use. The review searched nine database sources until May 2022. Study quality was assessed using the CASP checklist and the COREQ criteria. A thematic synthesis was performed. Thirteen studies were included in the review. Nine studies were of GPs' perspectives, one study of psychiatrists', and three of a mix of HPs. Barriers and facilitators to discontinuing long-term AD yielded eight themes, ordered chronologically according to the considerations that HPs make when they review a long-term AD: perception of AD use, fears, HP role and responsibility, HPs attitude towards discontinuation, HPs confidence regarding ability to stop AD, perceived patient readiness to stop, support from relatives and support from other HP. Deprescribing long-term AD is a difficult and complex process for HPs. The review found evidence that the barriers far outweigh the facilitators. More education on the lack of evidence for the long-term effect of AD and the risks of long-term use, guidance on managing long-term use, and support for HPs and patients is needed to increase long-term AD discontinuation. Further research from an HP perspective other than GPs is required and should also explore how HPs can be supported in managing discontinuation ADs.

Treatment Results of High-dose-rate Brachytherapy and External Beam Radiation With Long-term Androgen Deprivation Therapy for Patients With Metastatic Prostate Cancer.

A recent clinical trial indicated the usefulness of local radiation therapy of the prostate in patients with low-volume metastatic prostate cancer. High-dose-rate brachytherapy (HDR-BT) is used mainly for high-risk, localized, and locally advanced cases. However, few studies exist on the efficacy of HDR-BT and external beam radiation therapy (EBRT) for metastatic prostate cancer. We conducted a retrospective analysis of 39 patients diagnosed with regional lymph node metastasis and/or a limited number of metastases who underwent HDR-BT and EBRT with long-term androgen deprivation therapy. We utilized Cox's proportional hazards models to identify predictors of oncological outcomes. Treatment outcomes, including biochemical recurrence-free survival (BCRFS), clinical progression-free survival (CPFS), and castration-resistant prostate cancer-free survival (CRPCFS), were compared according to the clinical stage. The median follow-up duration was 49 months (range=23-136 months). The 5-year BCRFS, CPFS, CRPCFS, and cancer-specific survival rates were 62.2%, 67.2%, 83.2%, and 93.4%, respectively. Based on Kaplan-Meier analysis, N1M0 and N0-1M1b showed favorable outcomes compared with N1M1a. Multivariate analysis revealed that N1M1a prostate cancer was an independent risk factor for poor BCRFS, CPFS, and CRPCFS. HDR-BT and EBRT with androgen deprivation therapy is a feasible approach for patients with newly diagnosed regional and low-metastatic-burden prostate cancer. However, in our cohort M1a prostate cancer had significantly inferior outcomes. A well-controlled prospective study is imperative to confirm our results.

Development and validation of an AI-derived digital pathology-based biomarker to predict benefit of long-term androgen deprivation therapy with radiotherapy in men with localized high-risk prostate cancer across multiple phase III NRG/RTOG trials.

5001 Background: Androgen deprivation therapy (ADT) improves survival and reduces risk of metastasis in men with high-risk localized prostate cancer (PC) receiving radiotherapy (RT). Predictive biomarkers are needed to guide ADT duration to maximize benefits and minimize risks. We sought to train and validate the first predictive biomarker for long-term (LT) vs short-term (ST) ADT using multiple phase III NRG Oncology randomized trials. Methods: Pre-treatment prostate biopsy slides were digitized from six phase III NRG/RTOG randomized trials of men receiving RT +/- ADT. The artificial intelligence (AI)-derived clinical and histopathological predictive biomarker was trained on RTOG 9408, 9413, 9902, 9910, and 0521 to predict differential benefit of LTADT on distant metastasis (DM). After the AI biomarker was locked, it was validated on RTOG 9202, which randomized men to RT + STADT (4 mo) vs LTADT (28 mo). The predictive utility of the AI biomarker was evaluated for the primary and secondary endpoints of DM and PC-specific mortality (PCSM), respectively, for ADT duration with Fine-Gray interaction models. Event rates were estimated by the cumulative incidence method. Deaths from other causes were treated as competing risks. Results: The AI-derived biomarker was trained on 2,641 men (median follow-up of 9.8 years, IQR [8.2, 11.5]) and validated on 1,192 men from RTOG 9202 (median follow-up of 17.2 years, IQR [9.1, 19.6]), where 80% had at least one high/very high (H/VH) risk feature (cT3-4, Gleason 8-10, PSA > 20, or primary Gleason pattern 5). Consistent with published results, LTADT significantly improved DM (subdistribution HR [sHR] 0.64, 95% CI 0.50-0.82, p < 0.001) in the validation cohort. The AI biomarker was prognostic for DM (sHR 2.35, 95% CI 1.72-3.19, p < 0.001). A significant biomarker-treatment interaction was observed (p = 0.04), in which AI-biomarker (+) men (n = 785, 66%) had reduced DM with LTADT (sHR 0.55, 95% CI 0.41-0.73, p < 0.001), but no benefit was observed (sHR 1.06, 95% CI 0.61-1.84, p = 0.84) for AI-biomarker (-) men (n = 407, 34%). The 10-year DM rate difference between RT + LTADT vs RT + STADT was 13% in AI-biomarker (+) men vs 2% in AI-biomarker (-) men. Similar trends were observed for PCSM outcomes. Risk classification (NCCN intermediate [n = 221, 43% (+)] vs other H/VH risk [n = 954, 71% (+)]) was prognostic but not predictive of LTADT benefit. Conclusions: We have successfully validated the first predictive biomarker of LTADT benefit with RT in localized high-risk PC using an AI-derived digital pathology-based platform in the phase III NRG/RTOG 9202 trial. The predictive AI biomarker identified 34% of men that could derive similar benefit with STADT, avoiding the side effects of prolonged ADT, and 43% of intermediate risk men who would benefit from LTADT.

Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Prostate Cancer: The Safety Analysis of the Prostate Cancer Study-5, a Groupe de Radio-Oncologie Génito-Urinaire de Quebec Led Phase 3 Trial

The low α\β ratio of 1.2 to 2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated (HF) radiation therapy (RT). To date, no phase 3 randomized clinical trial has compared moderately HF RT with standard fractionation (SF) exclusively in high-risk PCa patients. We are reporting the safety of moderate HF RT in high-risk PCa in an initially noninferiority-designed phase 3 clinical trial. From February 2012 to March 2015, 329 high-risk PCa patients were randomized to receive either SF or HF RT. All patients received neoadjuvant, concurrent, and long-term adjuvant androgen deprivation therapy. Standard fractionation RT consisted of 76 Gy in 2 Gy per fraction to the prostate, where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT included concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The coprimary endpoints were acute and delayed toxicity at 6 and 24 months, respectively. The trial was originally designed as a noninferiority with a 5% absolute margin. Given the lower-than-expected toxicities in both arms, the noninferiority analysis was completely dropped. Of the 329 patients, 164 were randomized to the HF and 165 to the SF arms. In total, there were more grade 1 or worse acute gastrointestinal (GI) events in the HF arm, 102 versus 83 events in the HF and SF arm, respectively (P=.016). This did not remain significant at 8 weeks of follow-up. There were no differences in grade 1 or worse acute GU events in the 2 arms, 105 versus 99 events in the HF and SF arm, respectively (P=.3). At 24 months, 12 patients in the SF arm and 15 patients in the HF arm had grade 2 or worse delayed GI-related adverse events (hazard ratio, 1.32; 95% CI, 0.62-2.83; P=.482). There were 11 patients in the SF arm and 3 patients in the HF arm with grade 2 or higher delayed genitourinary (GU) toxicities (hazard ratio, 0.26; 95% CI, 0.07-0.94; P=.037). There were 3 grade 3 GI and one grade 3 GU delayed toxicities in the HF arm and 3 grade 3 GU and no grade 3 GI toxicities in the SF arm. No grade 4-toxicities were reported. This is the first study of moderate HF dose-escalated RT in exclusively high-risk patients with prostate cancer treated with long-term androgen deprivation therapy and pelvic RT. Although our data were not analyzed as a noninferiority, our results demonstrate that moderately HF RT is well-tolerated, similar to SF RT at 2 years, and could be considered an alternative to SF RT.

Metastatic prostate cancer management: 20 years of progress

Since 1940, patients with metastatic prostate cancer were given androgen deprivation therapy alone. In 2013, the addition of docetaxel improved progression-free survival and overall survival in patients with metastatic hormone-sensitive prostate cancer. 1 Gravis G Fizazi K Joly F et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013; 14: 149-158 Summary Full Text Full Text PDF PubMed Scopus (528) Google Scholar , 2 Sweeney CJ Chen YH Carducci M et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015; 373: 737-746 Crossref PubMed Scopus (1831) Google Scholar After 2013, the combination of abiraterone acetate plus prednisolone with androgen deprivation therapy increased overall survival, as did the addition of other androgen receptor signalling inhibitors (such as enzalutamide or apalutamide) to standard androgen deprivation therapy. 3 James ND de Bono JS Spears MR et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017; 377: 338-351 Crossref PubMed Scopus (1091) Google Scholar , 4 Davis ID Martin AJ Stockler MR et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019; 381: 121-131 Crossref PubMed Scopus (734) Google Scholar , 5 Chi KN Chowdhury S Bjartell A et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021; 39: 2294-2303 Crossref PubMed Scopus (124) Google Scholar In 2022, the triple combination of androgen deprivation therapy, docetaxel, and abiraterone or darolutamide showed improved overall survival compared with androgen deprivation therapy plus docetaxel. 6 Fizazi K Foulon S Carles J et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022; 399: 1695-1707 Summary Full Text Full Text PDF PubMed Scopus (112) Google Scholar , 7 Smith MR Hussain M Saad F et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022; 386: 1132-1142 Crossref PubMed Scopus (153) Google Scholar Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocolEnzalutamide and abiraterone should not be combined for patients with prostate cancer starting long-term androgen deprivation therapy. Clinically important improvements in survival from addition of abiraterone to androgen deprivation therapy are maintained for longer than 7 years. Full-Text PDF Open Access

Multi-Institutional Clinical Outcomes of Biopsy Gleason Grade Group 5 Prostate Cancers Treated With Contemporary High-Dose Radiation and Long-Term Androgen Deprivation Therapy

AimsThis multicentric retrospective study reports long-term clinical outcomes of non-metastatic grade group 5 prostate cancers treated with external beam radiotherapy (EBRT) alone with long-term androgen deprivation therapy (ADT). Materials and methodsPatients treated across 19 institutions were studied. The key endpoints that were evaluated were 5-year biochemical recurrence-free survival (bRFS), metastases-free survival (MFS), overall survival, together with EBRT-related acute and late toxicities. The impact of various prognostic factors on the studied endpoints was analysed using univariate and multivariate analyses. ResultsAmong the 462 patients, 88% (405) had Gleason 9 disease and 31% (142) had primary Gleason pattern 5. A prostate-specific membrane antigen positron emission tomography-computed tomography scan was used for staging in 33% (153), 80% (371) were staged as T3/T4 and 30% (142) with pelvic nodal disease. The median ADT duration was 24 months; 66% received hypofractionated EBRT and 71.4% (330) received pelvic nodal irradiation. With a median follow-up of 56 months, the 5-year bRFS, MFS and overall survival were 73.1%, 77.4% and 90.5%, respectively. Primary Gleason pattern 5 was associated with worse bRFS, MFS and overall survival with hazard ratios of 0.51 (95% confidence interval 0.35 to 0.73, P < 0.001), 0.64 (95% confidence interval 0.43 to 0.96, P = 0.031) and 0.52 (95% confidence interval 0.28 to 0.97, P = 0.040), respectively, whereas pelvic nodal disease was associated with worse bRFS (hazard ratio 0.67, 95% confidence interval 0.46 to 0.98, P = 0.039) and MFS (hazard ratio 0.56, 95% confidence interval 0.37 to 0.85, P = 0.006). The acute and late radiation-related toxicities were low overall and pelvic nodal irradiation was associated with higher toxicities. ConclusionContemporary EBRT and long-term ADT led to excellent 5-year clinical outcomes and low rates of toxicity in this cohort of non-metastatic grade group 5 prostate cancers. Primary Gleason pattern 5 and pelvic node disease portends inferior clinical outcomes.

Abstract 1451: Cognition-mediated transcriptomic signature associated with androgen deprivation therapy in prostate cancer

Abstract Androgen deprivation therapy (ADT) is the mainstay treatment for non-metastatic and metastatic hormone-sensitive prostate cancer. Long-term ADT treatment results in adverse side-effects in patients including depression, memory loss, cognitive decline, and dementia. We aimed to identify critical molecules that could provide link between brain-related changes and pathological mechanisms responsible for cognitive decline in prostate cancer patients on ADT protocol. For these studies, gene expression data (GSE150807 and GSE151083) of human prostate cancer cells exposed to enzalutamide emulating ADT protocol was used to identify differential expression of genes at the transcript level. RNA sequencing analysis identified 9409 and 7757 differentially expressed genes (DEGs) in LNCaP and C4-2B enzalutamide exposed cells at p-value &amp;lt; 0.0005 and FDR&amp;lt; 0.05. In both cell lines, neuronal receptor signaling pathway was significantly overrepresented at 0.05 FDR-adjusted p-value (q-value). The genes associated with neuronal receptor signaling pathway belong to the ligand-gated ion channel and G-protein coupled receptors. Validation studies using brain glial cells treated with enzalutamide showed significant upregulation (p-value 0.001) of GABRB1, GABRA3, GABBR2 (GABA receptors/ligand-gated ion channel), BDNF (brain-derived neurotrophic factor), IFNB1 (interferon beta 1), NR3C1 (nuclear receptor subfamily 3 group c member/glucocorticoid receptor), ATGR1 (type-1 angiotensin II receptor), GRIN1 (glutamate ionotropic receptor NMDA type submit 1/ligated-gated ion channel), GRIN2D (glutamate ionotropic receptor NMDA type submit 2D/ligated-gated ion channel). In brain neuronal cells, enzalutamide exposure resulted in increased expression of NR3C1 whereas GABA/ligand-gated ion channel and others were downregulated and/or statistically non-significant. Further analysis using DisGenET (cytoscape) highlighted ATGR1, GABRB1, GRIN1, GRIN2D, and NR3C1 association with neuronal diseases including cognition disorder, forgetfulness, depressive mood, and others. The results of our study provide the first proof of evidence linking cognitive decline, depression, memory loss, and other neurological disorder more likely to develop in prostate cancer patients undergoing long-term androgen deprivation therapy. Citation Format: Shiv Shankar Verma, Eswar Shankar, Vaibhav Singh, Vijay Krishna, Sanjay Gupta. Cognition-mediated transcriptomic signature associated with androgen deprivation therapy in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1451.

Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer

BackgroundBetween 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy.MethodsAt a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes).ResultsFollow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P=0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis.ConclusionsAfter 15 years of follow-up, prostate cancer–specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Association of intermittent or continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with nonmetastatic prostate cancer.

83 Background: Evidence on risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) in patients (pts) with nonmetastatic prostate cancer (nmPC) is mixed. This real-world study examined these risks in pts with nmPC receiving iADT or cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with nmPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, and who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment-weighted Cox regression models estimated the adjusted hazard ratio (aHR) of the outcomes. Subgroup analyses examined pts by CVD history. A sensitivity analysis restricted the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 10,655 pts were included; 2095 (20%) received iADT and 8560 (80%) cADT; 63% of iADT pts and 66% of cADT pts had baseline CVD history. Median follow-up was 44 and 48 months and time on ADT (excluding gaps for iADT pts) was 23 and 17 months for the iADT and cADT cohorts, respectively. In adjusted analyses, pts receiving cADT had a lower risk of MACE vs iADT. No difference in risk of endocrine/metabolic events was observed. Results for MACE were similar in pts with prior CVD history; however, there was no difference in risk of MACE in those without CVD history. Sensitivity analysis results for MACESA were similar to the main results. Conclusions: Pts with nmPC receiving cADT had a lower risk of MACE, and no difference in risk of endocrine/metabolic events, compared with iADT. There was no difference in risk of MACE in pts without a prior history of CVD. [Table: see text]

Association of intermittent vs continuous androgen deprivation therapy with cardiovascular disease and endocrine/metabolic disorders in patients with metastatic prostate cancer.

82 Background: There is mixed evidence on the risks of cardiovascular disease (CVD) and endocrine/metabolic disorders associated with long-term intermittent and continuous androgen deprivation therapy (iADT and cADT, respectively) for metastatic prostate cancer (mPC). This study examined these risks in patients (pts) with mPC receiving iADT vs cADT in the US. Methods: This was a retrospective cohort study of SEER-Medicare pts with mPC initiating ADT (2010–2017), with ≥36 months of continuous insurance coverage, unless death occurred, who did not receive chemotherapy or a second-generation anti-androgen during follow-up. iADT and cADT cohorts were defined by treatment patterns and gaps in therapy. Comorbidities and clinical events were identified using ICD-9/10-CM codes. Outcomes examined were major adverse cardiovascular events (MACE [myocardial infarction (MI), stroke, cardiomyopathy/heart failure (HF), pulmonary embolism (PE), ischemic heart disease (IHD), or all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, or osteoporosis). Inverse probability of treatment weighting (IPTW) was used to adjust for differences between cohorts; weighted Cox models were used to estimate the hazard ratio (HR) of the outcomes. Subgroup analyses examined pts by CVD history; a sensitivity analysis was performed restricting the definition of MACE to include CVD-related mortality as a component, i.e., MACESA (MI, stroke, cardiomyopathy/HF, PE, IHD, or CVD-related mortality). Results: 2234 pts with mPC were included; 478 (21%) received iADT and 1756 (79%) cADT. Median follow-up time was 27 and 13 months, and time on ADT (excluding gaps for iADT pts) was 24 and 19 months for the iADT and cADT cohorts, respectively. Deaths occurred in 39% of iADT pts vs 55% of cADT pts; PC was the most common cause of death in both cohorts. In adjusted analyses, pts receiving cADT had a higher risk of MACE vs iADT. No differences in risk of endocrine/metabolic events were observed. Subgroup analysis showed that baseline history of CVD did not alter the results for MACE. Sensitivity analysis results showed no difference in risk of MACESA between pts receiving cADT vs iADT. Conclusions: Pts with mPC receiving cADT had a higher risk of MACE (including all-cause mortality), and no difference in risk of endocrine/metabolic events, compared with those receiving iADT. When MACE was restricted to include CVD-related mortality, there was no difference in risk between cohorts. [Table: see text]

Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3 Randomized Trials

Decipher is a genomic classifier (GC) prospectively validated postprostatectomy. We validated the performance of the GC in pretreatment biopsy samples within the context of 3 randomized phase 3 high-risk definitive radiation therapy trials. A prespecified analysis plan (NRG-GU-TS006) was approved to obtain formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled in the NRG/Radiation Therapy Oncology Group (RTOG) 9202, 9413, and 9902 phase 3 randomized trials. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays and GC scores were obtained. The primary objective was to validate the independent prognostic ability for the GC for distant metastases (DM), and secondary for prostate cancer-specific mortality (PCSM) and overall survival (OS) with Cox univariable and multivariable analyses. GC scores were obtained on 385 samples, of which 265 passed microarray quality control (69%) and had a median follow-up of 11 years (interquartile range, 9-13). In the pooled cohort, on univariable analysis, the GC was shown to be a prognostic factor for DM (per 0.1 unit; subdistribution hazard ratio [sHR], 1.29; 95% confidence interval [CI], 1.18-1.41; P < .001), PCSM (sHR, 1.28; 95% CI, 1.16-1.41; P < .001), and OS (hazard ratio [HR], 1.16; 95% CI, 1.08-1.22; P < .001). On multivariable analyses, the GC (per 0.1 unit) was independently associated with DM (sHR, 1.22; 95% CI, 1.09-1.36), PCSM (sHR, 1.23; 95% CI, 1.09-1.39), and OS (HR, 1.12; 95% CI, 1.05-1.20) after adjusting for age, Prostate Specific Antigen, Gleason score, cT stage, trial, and randomized treatment arm. GC had similar prognostic ability in patients receiving short-term or long-term androgen-deprivation therapy, but the absolute improvement in outcome varied by GC risk. This is the first validation of a gene expression biomarker on pretreatment prostate cancer biopsy samples from prospective randomized trials and demonstrates an independent association of GC score with DM, PCSM, and OS. High-risk prostate cancer is a heterogeneous disease state, and GC can improve risk stratification to help personalize shared decision making.

A Comprehensive Overview of Small-Molecule Androgen Receptor Degraders: Recent Progress and Future Perspectives.

Prostate cancer (PC), the second most prevalent malignancy in men worldwide, has been proven to depend on the aberrant activation of androgen receptor (AR) signaling. Long-term androgen deprivation for the treatment of PC inevitably leads to castration-resistant prostate cancer (CRPC) in which AR remains a crucial oncogenic driver. Thus, there is an urgent need to develop new strategies to address this unmet medical need. Targeting AR for degradation has recently been in a vigorous development stage, and accumulating clinical studies have highlighted the benefits of AR degraders in CRPC patients. Herein, we provide a comprehensive summary of small-molecule AR degraders with diverse mechanisms of action including proteolysis-targeting chimeras (PROTACs), selective AR degraders (SARDs), hydrophobic tags (HyT), and other AR degraders with distinct mechanisms. Accordingly, their structure-activity relationships, biomedical applications, and therapeutic values are also dissected to provide insights into the future development of promising AR degradation-based therapeutics for CRPC.

Evaluation of Patients with Localized Prostate Cancer in whom Long-Term Successful Androgen Deprivation Therapy was Ceased

We evaluated the clinical course of patients with localized prostate cancer in whom long-term successful androgen deprivation therapy (ADT) was ceased. Study subjects were 24 patients with stage B prostate cancer who were initially treated with ADT for a median duration of 93 months. The median age at the cessation of ADT was 84 years. The median nadir serum prostate specific antigen (PSA) level was 0.022 ng/ml. The median duration of follow-up from the cessation of ADT was 31 months. During follow-up, five patients showed PSA elevation of ≥2 ng/ml from the nadir. Serum testosterone level was tested in 20 patients, and five showed testosterone recovery ≥0.5 ng/ml. Seven patients died from diseases other than prostate cancer, but there were no deaths caused by prostate cancer. This study demonstrated that long-term successful ADT for localized prostate cancer could be ceased with adequate follow-up evaluation.

P059 - Radical prostatectomy versus high-dose-rate brachytherapy and hypo-fractionated external beam radiation combined with long-term androgen deprivation for high-risk prostate cancer

P059 - Radical prostatectomy versus high-dose-rate brachytherapy and hypo-fractionated external beam radiation combined with long-term androgen deprivation for high-risk prostate cancer

PSOR5 Presentation Time: 11:50 AM: Interstitial Hyperthermia and High Dose-Rate Brachytherapy Combined with Short-Term Androgen Deprivation Therapy and External-Beam Radiation in High- and Very High-Risk Prostate Cancer

<h3>Purpose</h3> Multimodality treatment of high- and very-high risk prostate cancer has evolved tremendously in recent years to incorporate long-term androgen deprivation therapy (ADT), external-beam radiation therapy (EBRT), and brachytherapy, resulting in improved biochemical progression-free survival (bPFS). However, outcomes remain imperfect, and many patients are unwilling or unable to tolerate long-term ADT use. Existing studies show that hyperthermia is a potent and well-tolerated radiosensitizer. We report the outcomes of patients treated with short-term ADT, EBRT, and high dose-rate (HDR) brachytherapy combined with interstitial hyperthermia. <h3>Materials and Methods</h3> In a single-institution, retrospective study, we reviewed all patients with high- or very high-risk prostate adenocarcinoma who began definitive treatment between December 2016 and March 2020 with up to six months of ADT, whole-pelvis EBRT, and a combination of HDR brachytherapy boost and interstitial hyperthermia. Our primary endpoint was bPFS based on the Phoenix definition (PSA nadir +2 ng/mL) calculated from time of ADT initiation. We also report data on type of failure, survival, and toxicity. <h3>Results</h3> 56 patients were reviewed, including 21 with high-risk and 35 with very high-risk prostate adenocarcinoma. Median age was 72 years (range 52-82 years). Median duration of ADT use was 4 months (range 0-6 months). All patients received whole-pelvis EBRT of 45Gy/25fx. 55 patients (98%) received a 5.4Gy/3fx EBRT boost to the prostate and seminal vesicles. All patients received two Iridium-192 HDR implants to further boost the prostate and seminal vesicles, with each implant separated by at least one week (median 2 weeks, range 1-6 weeks) and consisting of two fractions of 5.5Gy separated by five to seven hours, for a total of 22Gy/4fx. All patients received at least one interstitial hyperthermia treatment of at least 45 minutes in between fractions of the same implant. 50 patients (89%) received both planned hyperthermia treatments of at least 60 minutes each at a goal temperature of 42-43 degrees Celsius. Median duration of follow-up was 28 months for all patients, with 34 months for high-risk and 28 months for very-high risk disease. The estimated two/three-year bPFS-rates were 100%/100% for high-risk and 92.0%/87.7% for very high-risk disease. Figure 1 represents the Kaplan-Meier curve for bPFS. Of the three very high-risk patients who failed biochemically, one failed regionally at 25 months, and two failed distantly at 15 and 23 months. There were no local failures. Two patients with very-high risk disease have died, both of unrelated lung disease at nine and 13 months. Four patients stopped their hyperthermia treatment early due to intolerance, with one developing an acute perineal burn that fully healed three months later. There were otherwise no grade 3 or higher acute toxicities. Four patients (7%) developed late grade 3 toxicities, all genitourinary-related. <h3>Conclusions</h3> Multimodality treatment of prostate cancer with short-term ADT, EBRT, HDR brachytherapy, and interstitial hyperthermia is safe and well-tolerated. For patients with high-risk disease, it provides excellent biochemical control while sparing long-term use of ADT. Patients with very high-risk disease may benefit from long-term use of ADT and/or other forms of systemic therapy. Longer follow-up and prospective trials are needed to validate our findings.

Accumulation of copy number alterations and clinical progression across advanced prostate cancer

BackgroundGenomic copy number alterations commonly occur in prostate cancer and are one measure of genomic instability. The clinical implication of copy number change in advanced prostate cancer, which defines a wide spectrum of disease from high-risk localised to metastatic, is unknown.MethodsWe performed copy number profiling on 688 tumour regions from 300 patients, who presented with advanced prostate cancer prior to the start of long-term androgen deprivation therapy (ADT), in the control arm of the prospective randomised STAMPEDE trial. Patients were categorised into metastatic states as follows; high-risk non-metastatic with or without local lymph node involvement, or metastatic low/high volume. We followed up patients for a median of 7 years. Univariable and multivariable Cox survival models were fitted to estimate the association between the burden of copy number alteration as a continuous variable and the hazard of death or disease progression.ResultsThe burden of copy number alterations positively associated with radiologically evident distant metastases at diagnosis (P=0.00006) and showed a non-linear relationship with clinical outcome on univariable and multivariable analysis, characterised by a sharp increase in the relative risk of progression (P=0.003) and death (P=0.045) for each unit increase, stabilising into more modest increases with higher copy number burdens. This association between copy number burden and outcome was similar in each metastatic state. Copy number loss occurred significantly more frequently than gain at the lowest copy number burden quartile (q=4.1 × 10−6). Loss of segments in chromosome 5q21-22 and gains at 8q21-24, respectively including CHD1 and cMYC occurred more frequently in cases with higher copy number alteration (for either region: Kolmogorov–Smirnov distance, 0.5; adjusted P<0.0001). Copy number alterations showed variability across tumour regions in the same prostate. This variance associated with increased risk of distant metastases (Kruskal-Wallis test P=0.037).ConclusionsCopy number alteration in advanced prostate cancer associates with increased risk of metastases at diagnosis. Accumulation of a limited number of copy number alterations associates with most of the increased risk of disease progression and death. The increased likelihood of involvement of specific segments in high copy number alteration burden cancers may suggest an order underlying the accumulation of copy number changes.Trial registrationClinicalTrials.gov NCT00268476, registered on December 22, 2005. EudraCT 2004-000193-31, registered on October 4, 2004.

Propensity score matching analysis comparing radical prostatectomy and radiotherapy with androgen deprivation therapy in locally advanced prostate cancer

To compare clinical outcomes between the use of robotic-assisted laparoscopic radical prostatectomy (RP) and radiotherapy (RT) with long-term androgen deprivation therapy (ADT) in locally advanced prostate cancer (PC), 315 patients with locally advanced PC (clinical T-stage 3/4) were considered for analysis retrospectively. Propensity score-matching at a 1:1 ratio was performed. The median follow-up period was 59.2 months (IQR 39.8–87.4). There were 117 (37.1%) patients in the RP group and 198 (62.9%) patients in the RT group. RT patients were older and had higher PSA at diagnosis, higher Gleason score grade group and more advanced T-stage (all p < 0.001). After propensity score-matching, there were 68 patients in each group. Among locally advanced PC patients, treatment with RP had a higher risk of biochemical recurrence compared to the RT group. In multivariate Cox regression analysis, treatment with RT plus ADT significantly decreased the risk of biochemical failure (HR 0.162, p < 0.001), but there was no significant difference in local recurrence, distant metastasis and overall survival (p = 0.470, p = 0.268 and p = 0.509, respectively). This information supported a clinical benefit in BCR control for patients undergoing RT plus long-term ADT compared to RP.

Common Iliac Node-Positive Prostate Cancer Treated With Curative Radiation Therapy: N1 or M1a?

Common iliac (CI) nodes are staged as (oligo)metastatic M1a for prostate cancer. Whether outcomes of pelvic node-positive (cN1) differ from CI node-positive (CI-M1a) prostate cancer after curative treatment is unclear. The present study compares outcomes in patients treated with radical whole pelvic radiation therapy (RT) and long-term androgen deprivation therapy (ADT). Patients with a node-positive adenocarcinoma prostate were identified, either CI-M1a or cN1, from a prospectively maintained database. More than 75% of patients were staged with Gallium (Ga) 68 prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) at the time of diagnosis. All patients received long-term ADT and moderately or extremely hypofractionated RT to the prostate and pelvis, including the CI region. At the time of biochemical failure (BCF), restaging was done with Ga68-PSMA-PET/CT to establish the patterns of failure. The CI-M1a cohort was classified as proximal or distal CI nodal location, and studied for outcomes. Of the 130 patients analyzed, 87 had cN1 and 43 had CI-M1a stage disease. The median duration of ADT before RT was 7 months, and total duration was at least 24 months. The majority of patients (65%) had Gleason grade group IV to V, and 75% had ≥T3 disease. After a median follow up of 61 months, BCF in the 2 groups was similar (cN1: n=21 of 87; 24.1%; CI-M1a: n=11 of 43; 25.6%; P=.86). At the time of BCF, restaging Ga68-PSMA-PET/CT located distant metastases in 20 of 32 patients (63%; 57% in cN1 and 73% in CI-M1a; P=.47). In addition, the 5-year biochemical failure-free (cN1: 77.4%; CI-M1a: 70.4%; P=.43), distant metastasis-free (cN1: 86.9%; CI-M1a: 79.4%; P=.23), and overall (cN1: 92.6%; CI-M1a 90.1%; P=.80) survival were similar in the 2 groups. Outcomes within CI-M1a were similar for proximal versus distal CI nodal location and 5-year biochemical failure-free survival (73.6% vs 58.6%; P=.81). Patients with oligometastatic CI-M1a and cN1 prostate cancer showed similar outcomes when treated with curative whole pelvic RT and long-term ADT. The treatment for these oligometastatic patients should be prospectively evaluated.

The future of PSMA PET and WB MRI as next-generation imaging tools in prostate cancer

Radiolabelled prostate-specific membrane antigen (PSMA)-based PET-CT has been shown in numerous studies to be superior to conventional imaging in the detection of nodal or distant metastatic lesions. 68Ga-PSMA PET-CT is now recommended by many guidelines for the detection of biochemically relapsed disease after radical local therapy. PSMA radioligands can also function as radiotheranostics, and Lu-PSMA has been shown to be a potential new line of treatment for metastatic castration-resistant prostate cancer. Whole-body (WB) MRI has been shown to have a high diagnostic performance in the detection and monitoring of metastatic bone disease. Prospective, randomized, multicentre studies comparing 68Ga-PSMA PET-CT and WB MRI for pelvic nodal and metastatic disease detection are yet to be performed. Challenges for interpretation of PSMA include tracer trapping in non-target tissues and also urinary excretion of tracers, which confounds image interpretation at the vesicoureteral junction. Additionally, studies have shown how long-term androgen deprivation therapy (ADT) affects PSMA expression and could, therefore, reduce tracer uptake and visibility of PSMA+ lesions. Furthermore, ADT of short duration might increase PSMA expression, leading to the PSMA flare phenomenon, which makes the accurate monitoring of treatment response to ADT with PSMA PET challenging. Scan duration, detection of incidentalomas and presence of metallic implants are some of the major challenges with WB MRI. Emerging data support the wider adoption of PSMA PET and WB MRI for diagnosis, staging, disease burden evaluation and response monitoring, although their relative roles in the standard-of-care management of patients are yet to be fully defined.

Docetaxel for Nonmetastatic Prostate Cancer: Long-Term Survival Outcomes in the STAMPEDE Randomized Controlled Trial.

BackgroundSTAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival.MethodsStandard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression).ResultsMedian follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity.ConclusionsThere is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases.