Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.

BACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.

BACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society.

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

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

Natural course of metastatic castration-resistant prostate cancer in the era of intensified androgen deprivation therapy in the hormone-sensitive setting.

BACKGROUND: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting. METHODS: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders. RESULTS: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group. CONCLUSION: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era.

High-dose vitamin D to attenuate bone loss in patients with prostate cancer on androgen deprivation therapy: A phase 2 RCT.

BACKGROUND: Androgen deprivation therapy (ADT) inhibits prostate cancer growth. However, ADT causes loss of bone mineral density (BMD) and an increase in fracture risk; effective interventions for ADT-induced bone loss are limited. METHODS: A phase 2 randomized controlled trial investigated the feasibility, safety, and preliminary efficacy of high-dose weekly vitamin D (HDVD, 50,000 IU/week) versus placebo for 24 weeks in patients with prostate cancer receiving ADT, with all subjects receiving 600 IU/day vitamin D and 1000 mg/day calcium. Participants were ≥60 years (mean years, 67.7), had a serum 25-hydroxyvitamin D level <32 ng/mL, and initiated ADT within the previous 6 months. At baseline and after intervention, dual-energy x-ray absorptiometry was used to assess BMD, and levels of bone cell, bone formation, and resorption were measured. RESULTS: The HDVD group (N = 29) lost 1.5% BMD at the total hip vs. 4.1% for the low-dose group (N = 30; p = .03) and 1.7% BMD at the femoral neck vs. 4.4% in the low-dose group (p = .06). Stratified analyses showed that, for those with baseline 25-hydroxyvitamin D level <27 ng/mL, the HDVD group lost 2.3% BMD at the total hip vs 7.1% for the low-dose group (p < .01). Those in the HDVD arm showed significant changes in parathyroid hormone (p < .01), osteoprotegerin (p < 0.01), N-terminal telopeptide of type 1 collagen (p < 0.01) and C-terminal telopeptide of type 1 collagen (p < 0.01). No difference in adverse events or toxicity was noted between the groups. CONCLUSIONS: HDVD supplementation significantly reduced hip and femoral neck BMD loss, especially for patients with low baseline serum 25-hydroxyvitamin D levels, although demonstrating safety and feasibility in prostate cancer patients on ADT.

Apalutamide for High-Risk Localized Prostate Cancer Following Radical Prostatectomy (Apa-RP).

PURPOSE: Approximately 25% to 50% of patients with high-risk localized prostate cancer experience biochemical recurrence (BCR) within 2 years of radical prostatectomy. The Apa-RP study (NCT04523207) investigated whether adjuvant apalutamide plus androgen deprivation therapy (ADT) in high-risk patients who have undergone radical prostatectomy improved BCR-free survival. MATERIALS AND METHODS: Apa-RP was a multicenter, open-label, single-arm, phase 2 study conducted in community urology practices in the US. High-risk patients who had radical prostatectomy received 12 cycles of apalutamide (240 mg daily; 28-day cycles) plus ADT. The primary end point was BCR-free survival. Secondary end points included testosterone recovery (≥150 ng/dL) and safety. RESULTS: One hundred eight patients were enrolled; median age was 66.0 years (range 46.0-77.0 years). Median preoperative PSA and baseline testosterone were 7.6 ng/mL (range 2.2-62.7 ng/mL) and 340.0 ng/dL (range 43.0-939.0 ng/dL), respectively. The BCR-free rate at 24 months (12 months after completion of planned therapy) was 100% (90% CI 93-100). Serum testosterone recovery rate (≥50 and ≥150 ng/dL) 12 months after treatment completion was 96% (95% CI 88-98) and 77% (95% CI 66-85), respectively. Overall, 107 (99%) patients experienced treatment-emergent adverse events, with 24 (22%) experiencing grade 3 to 4 events. CONCLUSIONS: In Apa-RP, BCR-free survival was 100% with 77% of patients having testosterone recovery (≥150 ng/dL) within 12 months of actual treatment completion and a manageable safety profile. These results provide proof of concept that treatment intensification with 12 cycles of apalutamide plus ADT could become an option for patients with high-risk localized prostate cancer who have undergone radical prostatectomy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04523207.

Protocol for CHAMPION study: a prospective study of maximal-cytoreductive therapies for patients with de novo metastatic hormone-sensitive prostate cancer who achieve oligopersistent metastases during systemic treatment with apalutamide plus androgen deprivation therapy.

BACKGROUND: The proposed trial is to examine the feasibility of prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided cytoreduction plus apalutamide and androgen deprivation therapy (ADT) for newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) at oligometastatic state. METHODS: CHAMPION (NCT05717582) is an open-label, single-arm, phase II trial, planning to enroll newly diagnosed mHSPC cases with oligometastases (≤ 10 distant metastatic sites in conventional imaging). Patients will receive 6 cycles of apalutamide plus ADT. Patients with oligometastatic disease at PSMA PET/CT after 3 treatment cycles will receive cytoreductive radical prostatectomy. PSMA PET/CT-guided metastasis-directed external radiation therapy will be determined by the investigators. Apalutamide plus ADT will be continued for 2 weeks postoperatively. The primary endpoint is the proportion of patients with undetectable prostate-specific antigen (PSA), no disease progression, and no symptom deterioration after 6 cycles of apalutamide plus ADT. Secondary endpoints include the percentage of patients with PSA ≤ 0.2 ng/mL and oligometastases by the end of 3 treatment cycles, PSA response rate, and safety. Fleming's two-stage group sequential design will be adopted in the study, where the null hypothesis is that the rate of patients with an undetectable PSA is ≤ 40% after 6 cycles of treatment, while the alternate hypothesis is an undetectable PSA of > 60%; with one-sided α = 0.05, power = 0.80, and an assumed dropout rate of 10%, the required number of patients for an effective analysis is 47. Enrolment in the study commenced in May 2023. DISCUSSION: The multi-modal therapy based on treatment response may improve the prognosis of newly diagnosed mHSPC patients with oligometastases. TRIAL REGISTRATION: The study is registered with Clinical Trials.Gov (NCT05717582). Registered on 8th February 2023.

A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma - the DUCT study protocol.

BACKGROUND: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients. METHODS: This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome. DISCUSSION: The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022. PROTOCOL VERSION: Current protocol version 4.0, February 21, 2024.

Protocol of a drug-drug interaction study between bictegravir/emtricitabine/tenofovir alafenamide and feminizing hormones in trans women living with HIV.

AIMS: Trans/transfeminine women are disproportionally affected by HIV. Concerns regarding negative drug-drug interactions (DDIs) between ART drugs and gender-affirming hormone therapy (GAHT), specifically feminizing hormone therapy (FHT), may contribute to the lower ART uptake by trans women with HIV compared with their cis counterparts. The aim of this study is to investigate the bidirectional pharmacokinetic effects of components of FHT regimens (oral oestradiol and androgen-suppressing medications) with the ART regimen (bictegravir/emtricitabine/tenofovir alafenamide [B/F/TAF)]. METHODS: We present a protocol for a three-armed, parallel-group, longitudinal (6-month), DDI study. Group 1 includes 15 3trans women with HIV taking FHT and ART; group 2 includes 15 premenopausal cis women with HIV taking ART; group 3 includes 15 trans women without HIV taking FHT. Women with HIV must be on or switch to B/F/TAF at baseline and be virally suppressed for ≥3 months. Trans women must be taking a stable regimen of ≥2 mg daily oral oestradiol and an anti-androgen (pharmaceutical, and/or surgical, and/or medical) for ≥3 months. Plasma ART drug concentrations will be sampled at Month 2 and compared between groups 1 and 2. Serum oestradiol concentrations will be sampled at baseline and Month 2 visits and compared between groups 1 and 3. The primary outcomes are B/F/TAF pharmacokinetic parameters (Cmin, Cmax and AUC) and oestradiol concentrations (Cmin, C4h, Cmax and AUC) at month 2. DISCUSSION: This study is of global importance as it provides critical information regarding safe coadministration of B/F/TAF and FHT, both of which are life-saving therapies for trans women with HIV.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

A retrospective study of prognostic factors and prostate-specific antigen dynamics in Japanese patients with metastatic hormone-sensitive prostate cancer who received combined androgen blockade therapy with bicalutamide.

BACKGROUND: This retrospective observational study explored the therapeutic potential of combined androgen blockade (CAB) with bicalutamide (Bic-CAB) as an initial treatment for metastatic hormone-sensitive prostate cancer (mHSPC) in Japan. METHODS: The electronic health records of 159 patients with mHSPC from three Japanese institutions who received initial treatment with Bic-CAB between 2007 and 2017 were analyzed. The time to prostate-specific antigen (PSA) progression, duration of Bic-CAB treatment, and overall survival (OS), with various definitions for PSA progression, were assessed. A multivariate Cox proportional hazards model was constructed using clinical parameters to predict time to the end of Bic-CAB treatment and OS. RESULTS: The median observation period was 46.4 months, and the median age of patients at diagnosis was 71 years. A total of 46.5% patients experienced PSA progression with a median survival duration of 29 months (according to Prostate Cancer Clinical Trials Working Group 3 criteria), and 49.1% patients achieved a PSA nadir < 0.2 ng/mL in a median time of 4.7 months. When stratified by PSA nadir and PSA change, patients at low risk for disease progression with a small PSA change due to low initial PSA had a 5-year OS of 100% and a 10-year OS of 75%. The OS during the observation period was 72.9 months. CONCLUSION: These findings highlight the potential effect of Bic-CAB in patients with mHSPC who were at low risk for disease progression. Initial treatment with Bic-CAB and adjusting treatment early based on PSA dynamics may be a reasonable treatment plan for these patients.

Prognostic outcomes in Japanese patients with metastatic castration-sensitive prostate cancer: Comparative assessments between conventional androgen deprivation therapy (ADT) and ADT with novel androgen receptor signal inhibitor.

OBJECTIVE: The objective of this study was to compare the prognostic outcomes between metastatic castration-sensitive prostate cancer (mCSPC) patients receiving conventional androgen deprivation therapy (ADT) and those receiving ADT plus a novel androgen-receptor signaling inhibitor (ARSI) in routine clinical practice in Japan. METHODS: This was conducted as a retrospective multicenter study including 581 mCSPC patients, consisting of 305 receiving ADT alone or in combination with bicalutamide (group 1) and 276 receiving ADT plus one of the following ARSIs: abiraterone acetate, apalutamide, or enzalutamide (group 2). Prognostic outcomes between these 2 groups were comprehensively compared. RESULTS: In the entire cohort, prostate-specific antigen-progression-free survival (PSA-PFS) in group 2 was significantly longer than that in group 1, while no significant difference was noted in overall survival (OS) between the two groups. In patients corresponding to the LATITUDE high-risk group, however, both PSA-PFS and OS in group 2 were significantly longer than those in group 1. Of several factors examined, the following were identified as independent predictors of poor PSA-PFS in the entire cohort as well as the LATITUDE high-risk group: high C-reactive protein, high lactate dehydrogenase, high alkaline phosphatase, high Gleason score, and group 1. Furthermore, it was possible to precisely classify both the entire cohort and LATITUDE high-risk group into 3 risk groups regarding PSA-PFS according to the positive numbers of independent factors: positive for ≤1 factor, favorable; 2 factors, intermediate; and ≥3 factors, poor. CONCLUSION: Combined use of ARSIs with ADT could improve the prognostic outcomes of mCSPC patients, particularly those in the LATITUDE high-risk group, in real-world clinical practice in Japan.

Functional Outcomes After Localized Prostate Cancer Treatment.

Importance: Adverse outcomes associated with treatments for localized prostate cancer remain unclear. Objective: To compare rates of adverse functional outcomes between specific treatments for localized prostate cancer. Design, Setting, and Participants: An observational cohort study using data from 5 US Surveillance, Epidemiology, and End Results Program registries. Participants were treated for localized prostate cancer between 2011 and 2012. At baseline, 1877 had favorable-prognosis prostate cancer (defined as cT1-cT2bN0M0, prostate-specific antigen level <20 ng/mL, and grade group 1-2) and 568 had unfavorable-prognosis prostate cancer (defined as cT2cN0M0, prostate-specific antigen level of 20-50 ng/mL, or grade group 3-5). Follow-up data were collected by questionnaire through February 1, 2022. Exposures: Radical prostatectomy (n = 1043), external beam radiotherapy (n = 359), brachytherapy (n = 96), or active surveillance (n = 379) for favorable-prognosis disease and radical prostatectomy (n = 362) or external beam radiotherapy with androgen deprivation therapy (n = 206) for unfavorable-prognosis disease. Main Outcomes and Measures: Outcomes were patient-reported sexual, urinary, bowel, and hormone function measured using the 26-item Expanded Prostate Cancer Index Composite (range, 0-100; 100 = best). Associations of specific therapies with each outcome were estimated and compared at 10 years after treatment, adjusting for corresponding baseline scores, and patient and tumor characteristics. Minimum clinically important differences were 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, and 4 to 6 for bowel and hormone function. Results: A total of 2445 patients with localized prostate cancer (median age, 64 years; 14% Black, 8% Hispanic) were included and followed up for a median of 9.5 years. Among 1877 patients with favorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -12.1 [95% CI, -16.2 to -8.0]), but not worse sexual function (adjusted mean difference, -7.2 [95% CI, -12.3 to -2.0]), compared with active surveillance. Among 568 patients with unfavorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -26.6 [95% CI, -35.0 to -18.2]), but not worse sexual function (adjusted mean difference, -1.4 [95% CI, -11.1 to 8.3), compared with external beam radiotherapy with androgen deprivation therapy. Among patients with unfavorable prognosis, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel (adjusted mean difference, -4.9 [95% CI, -9.2 to -0.7]) and hormone (adjusted mean difference, -4.9 [95% CI, -9.5 to -0.3]) function compared with radical prostatectomy. Conclusions and Relevance: Among patients treated for localized prostate cancer, radical prostatectomy was associated with worse urinary incontinence but not worse sexual function at 10-year follow-up compared with radiotherapy or surveillance among people with more favorable prognosis and compared with radiotherapy for those with unfavorable prognosis. Among men with unfavorable-prognosis disease, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel and hormone function at 10-year follow-up compared with radical prostatectomy.

Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Transdermal oestradiol for androgen suppression in prostate cancer: long-term cardiovascular outcomes from the randomised Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme.

BACKGROUND: Androgen suppression is a central component of prostate cancer management but causes substantial long-term toxicity. Transdermal administration of oestradiol (tE2) circumvents first-pass hepatic metabolism and, therefore, should avoid the cardiovascular toxicity seen with oral oestrogen and the oestrogen-depletion effects seen with luteinising hormone releasing hormone agonists (LHRHa). We present long-term cardiovascular follow-up data from the Prostate Adenocarcinoma Transcutaneous Hormone (PATCH) trial programme. METHODS: PATCH is a seamless phase 2/3, randomised, multicentre trial programme at 52 study sites in the UK. Men with locally advanced or metastatic prostate cancer were randomly allocated (1:2 from August, 2007 then 1:1 from February, 2011) to either LHRHa according to local practice or tE2 patches (four 100 µg patches per 24 h, changed twice weekly, reducing to three patches twice weekly if castrate at 4 weeks [defined as testosterone ≤1·7 nmol/L]). Randomisation was done using a computer-based minimisation algorithm and was stratified by several factors, including disease stage, age, smoking status, and family history of cardiac disease. The primary outcome of this analysis was cardiovascular morbidity and mortality. Cardiovascular events, including heart failure, acute coronary syndrome, thromboembolic stroke, and other thromboembolic events, were confirmed using predefined criteria and source data. Sudden or unexpected deaths were attributed to a cardiovascular category if a confirmatory post-mortem report was available and as other relevant events if no post-mortem report was available. PATCH is registered with the ISRCTN registry, ISRCTN70406718; the study is ongoing and adaptive. FINDINGS: Between Aug 14, 2007, and July 30, 2019, 1694 men were randomly allocated either LHRHa (n=790) or tE2 patches (n=904). Overall, median follow-up was 3·9 (IQR 2·4-7·0) years. Respective castration rates at 1 month and 3 months were 65% and 93% among patients assigned LHRHa and 83% and 93% among those allocated tE2. 157 events from 145 men met predefined cardiovascular criteria, with a further ten sudden deaths with no post-mortem report (total 167 events in 153 men). 26 (2%) of 1694 patients had fatal cardiovascular events, 15 (2%) of 790 assigned LHRHa and 11 (1%) of 904 allocated tE2. The time to first cardiovascular event did not differ between treatments (hazard ratio 1·11, 95% CI 0·80-1·53; p=0·54 [including sudden deaths without post-mortem report]; 1·20, 0·86-1·68; p=0·29 [confirmed group only]). 30 (34%) of 89 cardiovascular events in patients assigned tE2 occurred more than 3 months after tE2 was stopped or changed to LHRHa. The most frequent adverse events were gynaecomastia (all grades), with 279 (38%) events in 730 patients who received LHRHa versus 690 (86%) in 807 patients who received tE2 (p<0·0001) and hot flushes (all grades) in 628 (86%) of those who received LHRHa versus 280 (35%) who received tE2 (p<0·0001). INTERPRETATION: Long-term data comparing tE2 patches with LHRHa show no evidence of a difference between treatments in cardiovascular mortality or morbidity. Oestrogens administered transdermally should be reconsidered for androgen suppression in the management of prostate cancer. FUNDING: Cancer Research UK, and Medical Research Council Clinical Trials Unit at University College London.

Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer.

BACKGROUND: The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear. METHODS: We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed. RESULTS: A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed. CONCLUSIONS: Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).

Efficacy and safety of Androgen Deprivation Therapy (ADT) combined with modified docetaxel chemotherapy versus ADT combined with standard docetaxel chemotherapy in patients with metastatic castration-resistant prostate cancer: study protocol for a multicentre prospective randomized controlled trial.

BACKGROUND: Androgen deprivation therapy (ADT) combined with docetaxel chemotherapy is the standard treatment for metastatic castration-resistant prostate cancer (mCRPC) patients. However, mCRPC patients are mainly frail elderly men, constantly accompanied by comorbidities and showing poor tolerance to standard docetaxel chemotherapy. Some exploratory studies administering modified chemotherapy regimens have reported noninferior oncologic outcomes with fewer adverse events, yet most are retrospective or small studies, and prospective randomized controlled trials have rarely been conducted. Therefore, we designed this modified docetaxel chemotherapy regimen in patients with mCRPC, aiming to evaluate its efficacy and safety compared with the standard docetaxel chemotherapy regimen. METHODS: This is an open-label, multi-institutional, prospective, randomized non-inferiority trial. A total of 128 patients with mCRPC will be randomized to receive ADT combined with modified docetaxel chemotherapy (experimental group, n=64) or ADT combined with standard docetaxel chemotherapy (control group, n=64). Patients in the experimental group will receive a modified regimen with docetaxel 40 mg/m2 on the 1st day and 35 mg/m2 on the 8th day, repeated every 21 days. The primary endpoint is progression-free survival at 2 years. Secondary endpoints include overall survival, prostate-specific antigen response rate, pain response rate, toxicity and quality of life. DISCUSSION: The expected benefit for the patient in the experimental arm is noninferior efficacy with decreased toxicity and improved quality of life compared with that in the control arm. To the best of our knowledge, this will be the first multicentre prospective randomized study to assess the efficacy and safety of modified docetaxel chemotherapy in patients with mCRPC in China. The results of this trial may provide benefit to mCRPC patients, especially those with poor performance. TRIAL REGISTRATION: chictr.org.cn Identifier: ChiCTR2100046636 (May 24, 2021). Ongoing study.

Darolutamide and survival in metastatic, hormone-sensitive prostate cancer: a patient and caregiver perspective and plain language summary of the ARASENS trial.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about the ARASENS trial, which was published in the New England Journal of Medicine in February 2022. The trial includes 1,306 men with a type of prostate cancer called metastatic, hormone-sensitive prostate cancer (also called mHSPC). In the trial, researchers wanted to learn if combining a treatment called darolutamide (also known by the brand name Nubeqa®) with two other medicines called androgen deprivation therapy (also called ADT) and docetaxel (brand name Taxotere®) could help treat patients with mHSPC better than placebo plus ADT and docetaxel. ADT with docetaxel is a treatment used for patients with mHSPC. Darolutamide is an approved treatment for a different type of prostate cancer called non-metastatic, castration-resistant prostate cancer (also called nmCRPC). WHAT WERE THE RESULTS?: The trial results showed that combining darolutamide with ADT and docetaxel increased the chance of survival and lowered the risk of death by 32.5% compared to combining ADT and docetaxel with placebo instead. Compared to patients who received the placebo, patients who received darolutamide had a delay in: their cancer becoming castration-resistant worsening pain having cancer-related bone fractures or related symptoms needing additional therapies for cancer The percentage of trial patients who had medical problems during the trial, also called adverse events, was similar between trial patients who received darolutamide and those who received the placebo. WHAT DO THE RESULTS OF THE STUDY MEAN?: Combining darolutamide with ADT and docetaxel helped treat trial patients with mHSPC better than placebo with ADT and docetaxel. Darolutamide in combination with ADT and docetaxel could be a treatment option for patients with mHSPC. Patients should always talk to their doctors and nurses before making any decisions about their treatment. This summary also includes perspectives on the ARASENS trial and prostate cancer from 3 members of the patient community. ClinicalTrials.gov NCT number: NCT02799602.

Long-term outcomes of androgen deprivation therapy in prostate cancer among Japanese men over 80 years old.

This study aimed to analyze the survival rate and to examine the risk of death from prostate cancer when accounting for competing risk of death, in men aged ≥80 y treated with primary androgen deprivation therapy (ADT). Data of patients with prostate cancer who had received ADT were extracted from a nationwide community-based database established by the Japan Study Group for Prostate Cancer. Prognostic variables, including progression-free survival, cancer-specific survival, overall survival, and death rates were compared between men stratified by prostate cancer risk. Overall, 4760 patients older than 80 y were included. The proportion of low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer among super-elderly men was 9.5%, 14.6%, 48.8%, 9.0%, 3.2%, and 24.9%, respectively. Survival rates decreased with increasing risk stratification. The cumulative 5-y death rate by prostate cancer for low-, intermediate-, high-, or very high-risk, regional, and metastatic prostate cancer, was 0.92% (95% confidence interval [CI]: 0.2%-3.6%), 1.6% (95% CI: 0.8%-3.4%), 5.75% (95% CI: 4.25%-7.75%), 15.6% (95% CI: 11.6%-23.3%), 20.7% (95% CI: 13.1%-31.7%), and 36.9% (95% CI: 32.8%-41.4%), respectively. Our findings support that there is no need for immediate ADT for low- and intermediate-risk groups. Conversely, in high- or very high-risk, regional, and metastatic prostate cancer, more efforts for curative therapy and intensive therapy are needed in selected patients.

Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: A phase-2 nonrandomized clinical trial.

BACKGROUND: AR-V7-positive metastatic prostate cancer is a lethal phenotype with few treatment options and poor survival. METHODS: The two-cohort nonrandomized Phase 2 study of combined immune checkpoint blockade for AR-V7-expressing metastatic castration-resistant prostate cancer (STARVE-PC) evaluated nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg), without (Cohort 1) or with (Cohort 2) the anti-androgen enzalutamide. Co-primary endpoints were safety and prostate-specific antigen (PSA) response rate. Secondary endpoints included time-to-PSA-progression-free survival (PSA-PFS), time-to-clinical/radiographic-PFS, objective response rate (ORR), PFS lasting greater than 24 weeks, and overall survival (OS). RESULTS: Thirty patients were treated with ipilimumab plus nivolumab (N = 15, Cohort 1, previously reported), or ipilimumab plus nivolumab and enzalutamide (N = 15, Cohort 2) in patients previously progressing on enzalutamide monotherapy. PSA response rate was 2/15 (13%) in cohort 1 and 0/15 in cohort 2, ORR was 2/8 (25%) in Cohort 1 and 0/9 in Cohort 2 in those with measureable disease, median PSA-PFS was 3.0 (95% confidence interval [CI]: 2.1-NR) in cohort 1 and 2.7 (95% CI: 2.1-5.9) months in cohort 2, and median PFS was 3.7 (95% CI: 2.8-7.5) in cohort 1 and 2.9 (95% CI: 1.3-5.8) months in cohort 2. Three of 15 patients in cohort 1 (20%, 95% CI: 7.1%-45.2%) and 4/15 patients (26.7%, 95% CI: 10.5%-52.4%) in cohort 2 achieved a durable PFS lasting greater than 24 weeks. Median OS was 8.2 (95% CI: 5.5-10.4) in cohort 1 and 14.2 (95% CI: 8.5-NA) months in cohort 2. Efficacy results were not statistically different between cohorts. Grade-3/4 adverse events occurred in 7/15 cohort 1 patients (46%) and 8/15 cohort 2 patients (53%). Combined cohort (N = 30) baseline alkaline phosphatase and cytokine analysis suggested improved OS for patients with lower alkaline phosphatase (hazards ratio [HR], 0.30; 95% CI: 0.11-0.82), lower circulating interleukin-7 (IL-7) (HR, 0.24; 95% Cl: 0.06-0.93) and IL-6 (HR, 0.13; 95% Cl: 0.03-0.52) levels, and higher circulating IL-17 (HR, 4.53; 95% CI: 1.47-13.93) levels. There was a trend towards improved outcomes in men with low sPD-L1 serum levels. CONCLUSION: Nivolumab plus ipilimumab demonstrated only modest activity in patients with AR-V7-expressing prostate cancer, and was not sufficient to justify further exploration in unselected patients. Stratification by baseline alkaline phosphatase and cytokines (IL-6, -7, and -17) may be prognostic for outcomes to immunotherapy.