Long-term Androgen Deprivation Therapy Research Articles

Enhancing the anticancer effect of androgen deprivation therapy by monocarboxylate transporter 1 inhibitor in prostate cancer cells.

Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.

Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

Hypofractionated radiation therapy combined with androgen deprivation therapy for high-risk localized prostate cancer.

This study aimed to analyse the treatment outcomes of moderately hypofractionated radiation therapy (RT) combined with androgen deprivation therapy (ADT) and the prognostic implications of prostate-specific antigen (PSA) kinetics in high-risk localized prostate cancer. The medical records of 140 patients who underwent definitive RT (70 Gy in 28 fractions) combined with ADT were retrospectively reviewed. ADT consists of a gonadotropin-releasing hormone agonist and an anti-androgen. Clinical outcomes included the biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS) and prostate cancer-specific survival (PCSS). The BFR and CFR were stratified by the PSA nadir and the time to the PSA nadir, respectively. Acute and late genitourinary and gastrointestinal adverse events were also recorded. The 5-year BFR, CFR, OS and PCSS rates were 9.8%, 4.5%, 90.2% and 98.7%, respectively. Ninety-five (67.9%) patients achieved a PSA nadir of 0.01 ng/mL. Patients with a PSA nadir >0.01 ng/mL had a significantly higher BFR and CFR (BFR, P = 0.001; CFR, P = 0.027), even after adjusting for other prognostic factors [per 0.1 ng/mL; BFR, hazard ratio (HR) 4.440, P < 0.001; CFR, HR 4.338, P = 0.001]. However, the time to the PSA nadir and pre-RT PSA were not significantly associated with the BFR and CFR. Six patients (4.3%) reported grade 3 late adverse events, mostly haematuria and haematochezia. Definitive RT with moderate hypofractionation combined with long-term ADT showed good efficacy for high-risk localized prostate cancer. The lowest PSA nadir was significantly associated with a low recurrence rate, indicating the importance of PSA follow-up.

Prognostic Impact of Prostate-Specific Antigen at 6 Months After Radiotherapy in Localized Prostate Cancer: An Individual Patient Data Analysis of Randomized Trials.

We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT). Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment. Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL. PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.

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.

Effectiveness and safety of darolutamide as a component of combination therapy in patients with prostate cancer

Prostate cancer is an extremely important problem in current urologic oncology. For a long time, the golden standard of treatment of common forms of prostate cancer at the stage of distant metastases was androgen deprivation therapy directed at suppression of native testosterone level. Combination treatment using long-term androgen deprivation therapy and new generation antiandrogens is currently a scientifically substantiated conceptually new standard of therapy which has replaced treatment paradigm using androgen deprivation therapy as a monotherapy in patients with metastatic hormone-sensitive prostate cancer. The article presents the results of large trials performed in patients with metastatic hormone-sensitive prostate cancer and characterizes the role of one of the most effective and safe drugs, darolutamide, used to treat patients of this subgroup.

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

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

Outcomes in patients with high- and very high-risk localized prostate cancer treated with definitive IMRT and long-term hormone therapy.

The aim of this study was to evaluate the effectiveness of intensity-modulated radiation therapy in combination with long-term androgen deprivation therapy for high-risk and very high-risk localized prostate cancer while also investigating factors associated with the therapeutic effect. Men who fulfilled criteria for the National Comprehensive Cancer Network high-risk or very high-risk localized prostate cancer and were treated with definitive intensity-modulated radiation therapy (74-78Gy) of the prostate and the seminal vesicle combined with androgen deprivation therapy in our institution from 2007 to 2016 were identified (n=197). In principle, patients received androgen deprivation therapy for 3-6months before radiation, concurrently, and for 2years after completion of intensity-modulated radiation therapy. The median follow-up period was 96months. The 5-year and 10-year overall survival rates in the overall population were 96.9% and 89.3%, respectively. The 5-year and 10-year cumulative incidence rates of biochemical failure were 2.5% and 16.3% in the high-risk group, and 8.6% and 32.0% in the very high-risk group, respectively, indicating a significant difference between the two groups (P=0.023). Grade Group 5 and younger age (cutoff: 70years old) were independent predictors of recurrence (P=0.016 and 0.017, respectively). Patients exhibiting biochemical failure within <18months after completion of androgen deprivation therapy displayed an increased risk of cancer-specific mortality (P=0.039) when contrasted with those who had a longer interval to biochemical failure. Patients with the National Comprehensive Cancer Network very high-risk prostate cancer, particularly those with Grade Group 5 and younger age, showed worse outcomes following intensity-modulated radiation therapy and long-term androgen deprivation therapy.

H3K27 acetylation activated-PDLIM7 promotes castration-resistant prostate cancer progression by inducing O-Glycosylation of YAP1 protein

Castration-resistant prostate cancer (CRPC) is a fatal disease that evolves from prostate cancer due to drug resistance after long-term androgen deprivation therapy. In this study, we aimed to find novel molecular targets for treating CRPC. Through peptidome, we screened out polypeptides dysregulated in the serum of CRPC patients. According to RT-qPCR analysis and cell viability detection, we chose PDZ and LIM Domain 7 (PDLIM7) as the research object. As demonstrated by loss-of-function assays, silencing of PDLIM7 could suppress CRPC cell proliferation, migration, and angiogenesis. Moreover, PDLIM7 knockdown enhanced the sensitivity of CRPC cells to docetaxel treatment. Subsequently, we found that CBP/p300 increases the H3K27ac level in the PDLIM7 promoter to activate PDLIM7. Mechanism experiments such as IP and western blot revealed that PDLIM7 interacted with YAP1 to induce O-Glycosylation of YAP1 and thus stabilize YAP1 protein. Rescue assays demonstrated that PDLIM7 promoted the malignant processes of CRPC cells through YAP1. Finally, an animal study validated that PDLIM7 aggravated tumor growth. In conclusion, our findings highlighted the oncogenic role of PDLIM7 upregulated by CBP/p300-induced H3K27ac enhancement in CRPC by stabilizing YAP1.

Randomized Trial of Concomitant Hypofractionated Intensity Modulated Radiation Therapy Boost Versus Conventionally Fractionated Intensity Modulated Radiation Therapy Boost for Localized High-Risk Prostate Cancer (pHART2-RCT)

The aim of this work is to report on the results of a phase 2 randomized trial of moderately hypofractionated (MH) versus conventionally fractionated (CF) radiation therapy to the prostate with elective nodal irradiation. This was a single-center, prospective, phase 2 randomized study. Patients with high-risk disease (cT3, prostate-specific antigen level >20 ng/mL, or Gleason score 8-10) were eligible. Patients were randomized to either MH using a simultaneous integrated boost (68 Gy in 25 fractions to prostate; 48 Gy to pelvis) or CF (46 Gy in 23 fractions with a sequential boost to the prostate of 32 Gy in 16 fractions), with long-term androgen deprivation therapy. The primary endpoint was grade ≥2 acute gastrointestinal (GI) and genitourinary (GU) toxicity (Common Terminology Criteria for Adverse Events version 3.0). Secondary endpoints included late GI and GU toxicity, quality of life, and oncologic outcomes. One-hundred eighty patients were enrolled; 90 were randomized to and received MH and 90 to CF. The median follow-up was 67.4 months. Seventy-five patients (41.7%) experienced a grade ≥2 acute GI and/or GU toxicity, including 34 (37.8%) in the MH and 41 (45.6%) in the CF arms, respectively (P = .29). Late grade ≥2 GI (P = .07) and GU (P = .25) toxicity was not significantly different between arms; however, late grade ≥3 GI toxicity was worse in the MH group (P = .01). There were no statistically significant quality-of-life differences between the 2 treatments. There were no statistically significant differences observed in cumulative incidence of biochemical failure (P = .71) or distant metastasis (P = .31) and overall survival (P = .46). MH to the prostate and pelvis with androgen deprivation therapy for men with high-risk localized prostate cancer was not significantly different than CF with regard to acute toxicity, quality of life, and oncologic efficacy. However, late grade ≥3 GI toxicity was more common in the MH arm.

Pelvic Irradiation for Node-Positive Prostate Cancer After Prostatectomy: Long-Term Results of the Prospective PLATIN-4 and PLATIN-5 Trials

Purpose: After radical prostatectomy (RP), adjuvant or salvage radiation treatment in node-positive prostate cancer is offered to prevent systemic disease. Prospective long-term survival and toxicity data on patients with radiation for nodal disease is still scarce. This study evaluates safety and feasibility of salvage radiotherapy to the pelvic lymph nodes in node-positive prostate cancer after RP. Methods: Between 2009 and 2018, 78 patients with lymph node recurrence after RP (PLATIN-4) or after RP and PBRT (PLATIN-5) were treated with salvage pelvic lymph node radiotherapy (PLNRT) with boost to the involved nodes as field abutment (PLATIN-5) and boost to the prostate bed (PLATIN-4).ADT was started two months prior to radiation and recommended for 24 months. Primary endpoint was safety and feasibility of the IMRT/IGRT technique based on the rate of treatment discontinuations and incidence of CTCAE grade 3+-toxicity. Secondary endpoints were progression free survival (PFS) and overall survival (OS). Results: No treatment discontinuations were reported in either trial. Median OS was not reached in PLATIN-4 and was 117 months in PLATIN-5. Median PFS was 66 months in PLATIN-4 and 39 months in PLATIN-5. Late grade 3+ genitourinary and gastrointestinal toxicity was observed in 4% of patients at 24-months of follow-up. Conclusions: Salvage radiotherapy to the prostate bed and the pelvic lymphatic drainage combined with long-term ADT is a curative treatment option for patients with node-positive prostate cancer after RP with excellent infield disease control. PLNRT as field abutment after PBRT is feasible with long-term survival without suffering from high-grade toxicity.

Long-term Overall Survival after External Beam Radiotherapy for Localised Prostate Cancer

AimsKnowledge on survival probabilities is essential for determining optimal treatment strategies. We studied overall survival and associated prognostic factors in Dutch patients with localised prostate cancer (PCa) selected for external beam radiotherapy. Materials and methodsFor this single-centre retrospective cohort study, we identified all T1-T3 PCa patients (aged 55–80 years) in the radiotherapy planning database with a start date between January 2006 and December 2013, treated with 72–78 Gy in 2 Gy fractions to the prostate ± seminal vesicles (n = 1536). Long-term androgen deprivation therapy (ADT) was predominantly prescribed in the case of extracapsular disease (>T3). Overall survival was estimated using the Kaplan–Meier method. Prognostic factors were evaluated in Cox regression models for the intermediate-risk and high-risk groups. ResultsThe median follow-up was 12 years for patients who were alive. Ten-year survival rates were 79.0% for low-risk (n = 120), 59.9% for intermediate-risk (n = 430) and 56.8% for high-risk patients (n = 986). A higher age, higher comorbidity score, active smoking and Gleason score ≥8 had a statistically significant negative impact on overall survival at multivariable analysis. ADT was associated with superior overall survival in the high-risk group translating into overall survival rates similar to the intermediate-risk group. ConclusionsAlthough PCa patients selected for external beam radiotherapy are typically in good health, their comorbidity score and smoking habits appeared to be dominant predictors for overall survival. Overall survival rates within the high-risk group varied, showing improved overall survival with ADT prescription and worse overall survival in the case of Gleason score ≥8.

Trimodality Therapy With Iodine-125 Brachytherapy, External Beam Radiation Therapy, and Short- or Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer: Results of a Multicenter, Randomized Phase 3 Trial (TRIP/TRIGU0907)

This phase 3 randomized investigation was designed to determine whether 30 months of androgen deprivation therapy (ADT) was superior to 6 months of ADT when combined with brachytherapy and external beam radiation therapy (EBRT) for localized high-risk prostate cancer. This study was conducted at 37 hospitals on men aged 40 to 79 years, with stage T2c-3a, prostate-specific antigen >20 ng/mL, or Gleason score >7, who received 6 months of ADT combined with iodine-125 brachytherapy followed by EBRT. After stratification, patients were randomly assigned to either no further treatment (short arm) or 24 months of adjuvant ADT (long arm). According to the Phoenix definition of failure, the primary endpoint was the cumulative incidence of biochemical progression. Secondary endpoints included clinical progression, metastasis, salvage treatment, disease-specific mortality, overall survival, and grade 3+ adverse events. An intention-to-treat analysis was conducted using survival estimates determined using competing risk analyses. Of 332 patients, 165 and 167 were randomly assigned to the short and long arms, respectively. The median follow-up period was 9.2 years. The cumulative incidence of biochemical progression at 7 years was 9.0% (95% CI, 5.5-14.5) and 8.0% (4.7-13.5) in the short and long arms, respectively (P=.65). The outcomes of secondary endpoints did not differ significantly between the arms. Incidence rates of endocrine- and radiation-related grade 3+ adverse events for the short versus long arms were 0.6 versus 1.8% (P=.62) and 1.2 versus 0.6% (P=.62), respectively. Both treatment arms showed similar efficacy among selected populations with high-risk features. The toxicity of the trimodal therapy was acceptable. The present investigation, designed as a superiority trial, failed to demonstrate that 30-month ADT yielded better biochemical control than 6-month ADT when combined with brachytherapy and EBRT. Therefore, a noninferiority study is warranted to obtain further evidence supporting these preliminary results.

Associations of quantitative whole-body PSMA-PET metrics with PSA progression status under long-term androgen deprivation therapy in prostate cancer patients: a retrospective single-center study

PurposeTo evaluate whether quantitative whole-body (WB) PSMA-PET metrics under long-term androgen deprivation therapy (ADT) and/or androgen receptor signaling inhibitors (ARSi) are associated with PSA progression.MethodsPatients who underwent at least 2 68Ga-PSMA-11 PET/CT scans between October 2016 and April 2021 (n = 372) and started a new line of ADT ± ARSi between PET1 and PET2 were retrospectively screened for inclusion. We investigated the association between PCWG3-defined PSA progression status at PET2 and the following PSMA-PET parameters: appearance of new lesions on PET2, ≥ 20% increase in WB-PSMA tumor volume (WB-PSMA-VOL), progression of disease (PD) by RECIP 1.0, and ≥ 30% increase in WB-PSMA-SUVmean from PET1 to PET2. Spearman’s rank correlation coefficients and Fisher’s exact test were used to evaluate the associations.ResultsThirty-five patients were included: 12/35 (34%) were treated with ADT only and 23/35 (66%) with ARSi ± ADT. The median time between PET1 and PET2 was 539 days. Changes (%) in median PSA levels, WB-PSMA-SUVmean, and WB-PSMA-VOL from PET1 to PET2 were -86%, -23%, and -86%, respectively. WB-PSMA-VOL ≥ 20%, new lesions, RECIP-PD, and WB-PSMA-SUVmean ≥ 30% were observed in 5/35 (14%), 9/35 (26%), 5/35 (14%), and 4/35 (11%) of the whole cohort, in 3/9 (33%), 7/9 (78%), 3/9 (33%), and 2/9 (22%) of patients with PSA progression at PET2, and in 2/26 (8%), 2/26 (8%), 2/26 (8%), and 2/26 (8%) of patients without PSA progression at PET2 (p = 0.058, p < 0.001, p = 0.058, p = 0.238, respectively). Changes in PSA were correlated to percent changes in WB-PSMA-VOL and WB-PSMA-SUVmean (Spearman ρ: 0.765 and 0.633, respectively; p < 0.001).ConclusionChanges in PSA correlated with changes observed on PSMA-PET, although discordance between PSA and PSMA-PET changes was observed. Further research is necessary to evaluate if PSMA-PET parameters can predict progression-free survival and overall survival and serve as novel endpoints in clinical trials.

Effect of Adjuvant Chemotherapy in Highly Malignant Non-Metastatic Prostate Cancer: An Interim Analysis of Non-Randomized Comparative Trials.

Gleason grade group 5 (GG5) prostate cancers is aggressive with high metastatic rates and is not sensitive to androgen deprivation therapy (ADT). Even the presence of a limited (tertiary) Gleason pattern 5 component may have high aggressive biological behavior. This study aims to prospectively evaluate whether a non-androgen receptor pathway therapy - adjuvant chemotherapy could improve clinical outcomes among non-metastatic prostate cancer with the above highly malignant characters. This prospective non-randomized clinical trial included non-metastatic prostate cancer patients with pathologically proven Gleason score of 9-10 or tertiary Gleason pattern 5. Each subject was allowed to decide whether to receive four to six cycles chemotherapy of docetaxel after receiving a standard treatment (i.e., radical surgery ± radiotherapy or radical radiotherapy combined with long-term ADT). The primary endpoint was event-free survival (EFS). Event was defined as any of biochemical failure or imaging failure, or change of systemic therapy due to PSA arises, or death. The secondary end points were distant metastasis-free survival (MFS), overall survival (OS), and treatment-related adverse events. A total of 188 consecutive patients were enrolled from November 2019 to November 2022. Median prostate-specific antigen was 26.6 ng/ml. 52% had T3b to T4 disease, 27% had N1 disease. 140 patients received standard therapy only, and 48 patients received adjuvant chemotherapy after radical therapy. The median follow-up time was 18.4 (3.0-36.7) months. The estimated 36-month EFS of the chemotherapy group and the control group were 94.7% vs. 72.8% (p = 0.044). There were 1 event who added novel endocrine therapy in the chemotherapy group, and 21 events in the control group, including 6 cases of biochemical recurrence and 9 cases of lymph node and distant metastasis, 4 cases that changed systemic therapy and 2 cases died. The MFS of the two groups at 36 months were 100% and 90.7%, respectively (P = 0.143). After the 1:1 propensity score match, the EFS and MFS of the two groups were 94.7% and 80.8% (P = 0.069), and 100% and 93.1% (P = 0.132), respectively. The urinary toxicity of grade 2 and 3 in the chemotherapy group and the control group were 4.2% and 7.1% (P = 0.134) while the grade 2 rectal toxicity were 5.0% and 10.4% (P = 0.317), respectively. No grade 4 toxicity occurred. Considering the chemotherapy-related side effects, grade 3 or above toxicity were leukopenia (41.7%), alopecia (27.1%), thrombocytopenia (2.1%) and edema (2.1%). Results of this interim analysis shows that the addition of adjuvant chemotherapy after standard radical therapy tends to improve the overall recurrence and metastasis free survival of patients with highly malignant prostate cancer, and the adverse effects are tolerable, which should be confirmed by long-term follow-up results.

1770O Refining risk stratification in patients undergoing radiotherapy (RT) and long-term (lt) ADT for high-risk/locally advanced prostate cancer (HR/LA-PC): An individual patient data (IPD) analysis of randomized controlled trials (RCTs) from the ICECaP consortium

1770O Refining risk stratification in patients undergoing radiotherapy (RT) and long-term (lt) ADT for high-risk/locally advanced prostate cancer (HR/LA-PC): An individual patient data (IPD) analysis of randomized controlled trials (RCTs) from the ICECaP consortium

Health-Related Quality of Life at Five Years for a Randomized Trial of Tri-Modality Therapy with I-125 Brachytherapy, External Beam Radiation Therapy, and Short- vs. Long-Term Androgen Deprivation Therapy for High-Risk Localized Prostate Cancer (TRIP)

To describe the patient-reported health-related quality of life (HR-QoL) outcomes at five years for a multicenter randomized trial of tri-modality therapy with iodine-125 brachytherapy, external beam radiation therapy (EBRT), and short- versus long-term androgen deprivation therapy (ADT) for high-risk localized prostate cancer (TRIP/TRIGU0907). A total of 332 men with high-risk prostate cancer were randomized to either 6 months of ADT (n = 165) or 30 months of ADT (n = 167) in conjunction with combined modality radiation therapy. For the HR-QoL assessment, general HR-QoL and disease-specific HR-QoL were measured using the Japanese version of the Medical Outcomes Study 8-items Short-Form Health Survey (SF-8) and the Expanded Prostate Cancer Index Composite (EPIC). Patient-reported outcome questionnaires were filled out before ADT initiation, and five years after. Scores were reported as mean with the standard deviation. QoL end points were assessed as the change between pre and post treatment using paired student t-test. Changes in the International Prostate Symptom Scores (IPSS) score, including total score and subscores, were also evaluated. The study was powered according to the primary endpoint of biochemical progression free survival with HR-QoL as a secondary endpoint. In addition, recovery of testosterone level (300ng/dL or higher) was calculated as the cumulative incidence curve and compared between arms by log-rank test. The cumulative incidence of biochemical progression, and salvage ADT treatment were not different between the arms. Mean domain scores at baseline were well balanced between the two arms in all HR-QoL. There were no differences in the SF-8 assessment and the total and subscore EPIC assessments between the arms. The average sexual function score was lower in short arm versus long arm; 16.24 versus 20.24 at baseline, but not different at five years, 9.96 versus 7.78 (p = 0.164). There were no significant differences between the arms for the total and subscore IPSS. Significantly higher percentage of patients, 71.7% in the short arm recovered to a normal testosterone level at 6 years after the initiation of ADT compared to 43.2% in long arm (p<0.0001). At five years after ADT initiation, there were no significant differences in all score changes between the two arms with general HR-QoL and disease-specific HR-QoL. Most of HR-QoL returned to baseline level, and sexual function scores were low from baseline in this population. Two-years' adjuvant ADT did not affect HR-QoL at five years, although it significantly retarded testosterone recovery compared to 6 months of hormone therapy.

Phase III Study of Hypofractionated, Dose Escalation Radiotherapy vs. Conventional Pelvic Radiation Therapy followed by High Dose Rate Brachytherapy Boost for High Risk Adenocarcinoma of the Prostate (PCS VI): Acute Toxicity Results

The low α\β ratio of 1.2-2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of lager fraction size. We have recently shown (PCS5) that high risk prostate cancer patients can safely and effectively be treated with moderate hypofractionated radiation therapy (HF-RT). To date there has been no phase-III randomized clinical-trial comparing moderately HF-RT with EBRT and HDR boost (HDRB). We are reporting the acute safety of EBRT+HDRB compared to moderate HF-RT in this phase III Canadian trial. From January 2015-June 2022, 308 high-risk localized PCa patients were randomized to receive either HF-RT or EBRT+HDRB. All patients received neo-adjuvant, concurrent, and long-term adjuvant androgen deprivation therapy (ADT). EBRT+HDRB consisted of 46 Gy in 2 Gy per fraction to the pelvis and a 15 Gy in one fraction HDR boost within 3 weeks of EBRT. HF-RT include 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. Of the 308 patients, 148 received HF-RT and 144 EBRT+ HDRB. The remainder either withdrew from the study or were treated with standard (2 Gy per fraction) fractionation for technical reasons. In both intention to treat and as treated analysis, using log-Rank, there were more grade 1 or worse (G1+) acute GI and GU events and more G2+ acute GI events in the HF-RT than EBRT+HDRB. As treated analysis the acute G1+ and G2+ GI events were 92 vs 77 (60.1% vs. 53.5%; p < 0.017) and 21 vs 10 (13.7% vs. 6.9%; p = 0.052), respectively for HF-RT and EBRT + HDRB. Similarly, the G1+ acute GU events were 123 vs. 101 (80.4% vs.70.1%; p < 0.001) respectively for HF-RT and EBRT+HDRB. There were only four G3 GI and one G3 GU acute toxicities in both arms. No grade 4 toxicities were reported. This is the first study of EBRT+HDRB compared to moderate HF dose escalated RT in high-risk prostate cancer patients treated with long-term ADT and pelvic RT. Our results demonstrate that both treatment approaches are well-tolerated and that EBRT+HDRB carries less G2+ GI and G1+ GU acute toxicities.

Patient Reported Outcomes in High-Risk Prostate Cancer Patients with or without Testosterone Recovery after Androgen Deprivation Therapy

In a previous report from a randomized trial of 630 patients (pts), we showed that 18 months of androgen deprivation therapy (18m ADT) appears to be equally effective as 36 months (36m ADT) in high-risk prostate cancer (HRPC) pts. We performed the current analysis to evaluate quality of life (QOL) using the 25 items of EORTC PR25 validated tool in pts with or without testosterone (T) recovery after ADT. We selectedpts with no biochemical failure to avoid subsequent T variations due to reintroduction of ADT for recurrence. Patients receiving exactly 18 or 36m of ADT, survived more than one year (y) post randomization, had T measured at baseline and during follow-up and who completed QOL questionnaire entered this review. The 25 items were regrouped into 5 scales. All items and scales scores were linearly transformed to a 0-100 points scale. Serum T was measured at baseline then at each visit. We defined unrecovered testosterone as measured below the normal level. All items and scales scores were analyzed with general linear model and repeated measures to evaluate changes between pts with or without T recovery over time. T recovery was adjusted in a multivariable model including age, initial normal/unrecovered T and ADT (18 or 36m). P-value < 0.01 was considered statistically significant and a difference in mean scores of ≥10 points was considered clinically relevant. Patient-reported outcomes were filled out before treatments, every 6m during ADT, 4m after ADT and then once a year for 5y. Two hundred sixty nine of 630 pts met the eligibility criteria and were retained for the analysis. At a median follow-up of 14 years, 140/269 (52.0%) pts recovered T to normal level: 94/166 (56.6%) in 18m ADT and 46/103 (44.7%) in 36m ADT, p = 0.056. The median time to recovered T was significantly lower in 18m vs. 36m ADT (3.04 vs. 5.06 y, p<0.001). The global adherence to QOL questionnaires was 83.9% (2649/3156) and was similar between arms. Pts recovering T compared to those who did not, had a better QOL. 6/20 items [difficult to get enough sleep: get up frequently at night to urinate, blood in stool, hot flushes, feel less man, interested in sex, sexually active (with or without intercourse)] and 2/4 scales (treatment and sexual activity) were statistically significant (all p<0.01). 2 items were also clinically relevant: hot flushes and interested in sex. Hot flushes were clinically relevant (more than 10 point of difference) between 3.5 to 5y inclusively with maximum difference of 19.4 point. Interest in sex was clinically relevant with 13.1 point of difference at 3 years. T recoverypost long-term ADT is associated with a significantly improved QOL in patients with HRPC. Considering similar prostate cancer clinical outcomes and faster T recovery, our results suggest that 18m ADT may be the most appropriate ADT treatment duration for these patients.

200 Higher bone mineral density in prediabetes, diabetes and with increasing HbA1c in older Irish adults: results from the TUDA study

Abstract Background Patients with type II diabetes have higher Bone Mineral Density (BMD) but paradoxically have an increased fracture risk. However, less is known about the relationship between prediabetes and BMD or fracture risk. We aimed to evaluate the relationship between pre-diabetes, diabetes, HbA1c and BMD in older Irish adults. Methods Study participants were from a large cross-sectional study of adults aged &amp;gt;60 years; Trinity Ulster University Department of Agriculture (TUDA) study. Patients on treatment for osteoporosis, current or previous long-term glucocorticoids, aromatase inhibitors or androgen deprivation therapy were excluded. Diabetes was defined by self-report, use of diabetic medications or HBA1c ≥6.5% and after excluding same, prediabetes was defined as a HbA1c of 5.7–6.4%[1]. BMD was measured by DXA at the total hip and lumbar spine. The relationship between prediabetes, diabetes, HbA1c and BMD was explored in regression models. Results There were 2,127 participants and mean age was 70.0 ± 6.5 with 57.9% female. 17.7% had diabetes and 26% prediabetes. Compared to normoglycaemic participants, diabetics had higher BMD at the hip (p &amp;lt; 0.001) and spine (p = 0.007) and prediabetics higher BMD at the hip (p &amp;lt; 0.001) after adjusting for age, sex, body mass index, serum vitamin D, eGFR, smoking, alcohol intake and timed up and go. In multivariate analysis, increasing HbA1c in non-diabetics was also associated with greater BMD at the hip (p = 0.001) but not the spine. Conclusion This study demonstrates that BMD is increased in older adults with both diabetes and prediabetes and with increasing HbA1c in non-diabetics. Despite this, BMD is known to underestimate fracture risk in diabetics where a lower treatment threshold for starting osteoporosis medications is recommended. This might also hold true in prediabetes where altered BMD could affect material bone quality and fracture risk though studies are conflicting and more research is required.