Clinical efficacy of different androgen deprivation therapies for prostate cancer and evaluation based on dynamic-contrast enhanced magnetic resonance imaging.

Objective: To evaluate the clinical efficacy of different androgen deprivation therapies for prostate cancer (PCa) based on dynamic-contrast enhanced magnetic resonance imaging (DCE-MRI). Methods: 104 patients with PCa were studied, all of whom were treated with androgen deprivation therapy. The patients were divided into a continuous group (continuous androgen deprivation therapy) and an intermittent group (intermittent androgen deprivation therapy) by random number table method, 52 cases/group. The therapeutic effect and DCE-MRI indices were compared and the relationship between DCE-MRI indices and clinical efficacy and the evaluation value of therapeutic efficacy were analyzed. Results: The objective response rate (ORR) of the intermittent group was higher than that of the continuous group (p < 0.05), and there was no significant difference in disease control rate (DCR) between the two groups (p > 0.05). After treatment, volume transfer coefficient (Ktrans), reverse transfer constant (Kep), volume fraction (Ve), blood volume (BV), and blood flow (BF) in both groups were lowered, and those in the intermittent group were lower than the continuous group (p < 0.05). Ktrans, Kep, Ve, BF, and BV in the ORR group were lower than those in the non-ORR group (p < 0.05). Ktrans, Kep, Ve, BF, and BV were correlated with the therapeutic effect of PCa (p < 0.05). The AUC value of the combined detection of DCE-MRI indices in evaluating the therapeutic effect of PCa was greater than that of each index alone (p < 0.05). Conclusion: Compared with continuous androgen deprivation therapy, intermittent androgen deprivation therapy has better clinical efficacy in the treatment of PCa, and DCE-MRI indices are related to the treatment efficacy of PCa and have an evaluation value.

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.

Cardiovascular and Thromboembolic Events in Patients With Localized Prostate Cancer Receiving Intensified Neoadjuvant Androgen Deprivation: A Systematic Review and Meta-Analysis.

Several phase II trials have investigated neoadjuvant novel androgen receptor signaling inhibitors (ARSIs) in combination with androgen deprivation therapy (ADT) followed by radical prostatectomy (RP) in prostate cancer (PC) patients. However, data regarding complications of intense hormone therapy and surgical complications are scarce. Our objective was to evaluate the occurrence of cardiovascular (CV) and thromboembolic (TE) adverse events (AE) in patients with localized PC who have received intense neoadjuvant ADT followed by prostatectomy. A comprehensive search in MEDLINE, Embase, Scopus and conference abstracts was performed. The strategies were developed and applied for each electronic database on March 7th, 2023. Eligible studies included randomized and single-arm trials testing ARSIs prior to prostatectomy that adequately reported safety data regarding CV and TE AE, peri-operative complications, and mortality during therapy. Pooled incidence (PI) of AE with 95% confidence interval (95% CI) was estimated using a random effects model. Quality assessment and reporting followed Cochrane Collaboration Handbook and PRISMA guidelines. PROSPERO: CRD42022344104. Nine randomized controlled trials and three single-arm phase II trials were included, comprising 702 patients (702 patients for CV AE and 522 for perioperative complications). The neoadjuvant regimen was classified as monotherapy with ARSI (100 patients), combination therapy with ADT + ARSI (383 patients), or ADT + ARSI + ARSI (219 patients). The PI of TE within the perioperative interval was 4.2% (95% CI = 2.6%-6.6%, I2 = 0.0%, P = .65), and the PI for CV AE was 4.6% (95% CI = 3.1%-6.7%, I2 = 0.0%, P = .71). Seven deaths were reported, resulting in a PI of 2.2% (95% CI = 1.3%-3.8%, I2 = 0.0%, P = .99), of which two were considered treatment-related and occurred within the perioperative period. The PI of hypertension grade 3-5 was 7.3% (95% CI = 4.8%-11.0%, I2 = 38.8%, P = .04). CV and TE AE associated with intense neoadjuvant hormone therapy in patients with localized PC can occur in up to 4.6% of cases. Our data warns for further assessment of thrombotic risk and prophylactic anticoagulation in this setting.

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.

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.

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.

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.

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.

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.

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.

Social cognitive outcomes are associated with improvements in mobility performance following lifestyle intervention in prostate cancer patients undergoing androgen deprivation therapy.

OBJECTIVE: To compare the effects of an exercise and dietary intervention with those of standard-of-care management upon change in lift and carry performance and mobility-related self-efficacy beliefs and explore associations in prostate cancer patients undergoing androgen deprivation therapy. METHODS: 32 prostate cancer patients (M age = 66.2 years; SD = 7.8) undergoing androgen deprivation therapy were randomly assigned to a 3-month exercise and dietary lifestyle intervention (n = 16) or standard-of-care management (n = 16). Outcome assessments were obtained at baseline, 2- and 3-month follow-up. RESULTS: The lifestyle intervention resulted in significantly greater improvements in lift and carry performance (p = 0.01) at 2 Months (d = 1.01; p < 0.01) and 3 Months (d = 0.95; p < 0.01) and superior improvements in mobility-related self-efficacy at 2 Months (d = 0.38) and 3 Months (d = 0.58) relative to standard-of-care. Mobility-related self-efficacy (r = -.66; p = 0.006) and satisfaction with function (r = -.63; p = 0.01) were significantly correlated with lift and carry performance at 3 Months. CONCLUSIONS: The exercise and dietary lifestyle intervention yielded superior improvements in lift and carry performance and mobility-related self-efficacy relative to standard-of-care and key social cognitive outcomes were associated with more favorable mobility performance.

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.

The Role of Estrone in Feminizing Hormone Treatment.

CONTEXT: In trans women, hormone treatment induces feminization; however, the degree of feminization varies from person to person. A possible contributing factor could be estrone, a weak estrogen that interferes with the estrogen receptor. OBJECTIVE: We assessed whether estrone is involved in feminization induced by hormone treatment. METHODS: This prospective cohort study, with follow-up of 1 year, included 212 adult trans women at a gender identity clinic, who were starting gender-affirming hormone treatment between July 2017 and December 2019, median age 25 years. Change in fat percentage and breast development were assessed. RESULTS: After 12 months of hormone treatment, estrone concentration was 187 pmol/L (95% CI, 153-220) in transdermal and 1516 pmol/L (95% CI, 1284-1748) in oral estradiol users. Fat percentage increased by 1.2% (interquartile range [IQR], 0.3-4.8) in transdermal and 4.6% (IQR, 2.5-5.9) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+4.4% (95% CI, -4.0 to 13) per 100 pmol/L increase in estrone concentration) nor in oral estradiol users (-0.7% [95% CI, -1.7 to 0.3]). Breast volume increased by 69 mL (IQR, 58-134) in transdermal and 62 mL (IQR, 32-95) in oral estradiol users. This was not associated with estrone concentrations in transdermal (+14% [95% CI, -49 to 156] per 100 pmol/L increase in estrone concentration) nor oral estradiol users (+11% [95% CI -14 to 43]). CONCLUSIONS: Change in fat percentage and breast development in trans women were not associated with estrone concentrations nor with administration route. Therefore, measurement of estrone concentrations does not have a place in the monitoring of feminization in trans women.

Differences in sex hormone recovery profile after cessation of 12-week gonadotropin-releasing hormone antagonist versus agonist therapy.

BACKGROUND: Pharmacobiological behavior differs between gonadotropin-releasing hormone (GnRH) antagonists and GnRH agonists. However, reliable evidence clarifying the difference between them is limited. OBJECTIVES: We aimed to elucidate the difference in recovery profile between GnRH antagonist (degarelix) and GnRH agonist (leuprorelin acetate or goserelin acetate) as short-term (12 weeks) neoadjuvant androgen deprivation therapy (ADT) prior to 125I-transperineal prostate brachytherapy (TPPB) for localized prostate cancer. MATERIALS AND METHODS: This study was initially designed as a single-center, prospective, open-label, randomized controlled trial. The primary endpoint was a serum testosterone level above the castration range (>50 ng/dl) after the cessation of 12-week neoadjuvant ADT (GnRH antagonist or GnRH agonists). All patients underwent 12 weeks of neoadjuvant ADT. The recovery profiles of hormones, prostate-specific antigen, total prostate volume (TPV), bone mineral density, and quality of life scores were investigated. RESULTS: Testosterone recovery duration after the last injection was significantly longer in the GnRH antagonist arm than in the GnRH agonist arm (median, 27.3 vs. 4.8 weeks, p < 0.001). The serum levels of luteinizing hormone and follicle-stimulating hormone in the GnRH antagonist arm also remained significantly lower than those in the GnRH agonist arm between 16 and 24 weeks (p < 0.01). Meanwhile, reduction in TPV at the time of TPPB was comparable between both arms (p = 0.128). There were also no significant between-arm differences in the International Prostate Symptom Score and the International Index of Erectile Function scores. DISCUSSION AND CONCLUSION: The recovery patterns of hormonal profiles after short-term (12 weeks) neoadjuvant ADT differ between GnRH antagonists and GnRH agonists. The choice between these drugs matters and may have a clinical impact depending on the primary objective of ADT.

Eficacia y seguridad de apalutamida y enzalutamida en pacientes adultos con diagnóstico de cáncer de próstata resistente a la castración no metastásico (Actualización) / Efficacy and safety of apalutamide and enzalutamide in adult patients diagnosed with nonmetastatic castration-resistant prostate cancer (Update)

ANTECEDENTES: El presente documento se ha elaborado en el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021. La eficacia y seguridad de apalutamida y enzalutamida fue evaluada previamente en el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 047-SDEPFyOTS-DETS-IETSI-2019, en pacientes adultos con diagnóstico de cáncer de próstata resistente a la castración no metastásico (CPRCnm), con tiempo de duplicación del antígeno prostático específico (PSA, por sus siglas en inglés) menor o igual de 10 meses. En aquel dictamen, se evaluó la evidencia proveniente de los ensayos clínicos (EC) de fase III PROSPER que evaluó el uso de enzalutamida más la terapia de privación de andrógenos (ADT, por sus siglas en inglés) vs. placebo más ADT y SPARTAN que evaluó apalutamida más ADT vs. placebo más ADT. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar nueva evidencia científica sobre la eficacia y seguridad de apalutamida más ADT y enzalutamida más ADT, en comparación con ADT sola, en pacientes adultos con diagnóstico de CPRCnm con tiempo de duplicación del PSA ≤ 10 meses. La búsqueda bibliográfica se realizó en las bases de datos PubMed. The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan guías de práctica clínica (GPC) y evaluación de tecnologías sanitarias (ETS) incluyendo la National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), El Instituto de Calidad y Eficiencia en la Atención de la Salud (IQWiG, por sus siglas en alemán), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la OMS, el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en Oncología, tales como: European Society for Medical Oncology (ESMO), National Comprehensive Cancer Network (NCCN). Finalmente, se realizó una búsqueda en la página web de registro de EC, www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: Luego de la búsqueda bibliográfica, desde octubre de 2019 hasta agosto 2021, se identificaron 5 GPC desarrolladas por la National Comprehensive Cancer Network (NCCN)(NCCN 2021), la European Association of Urology (EAU), la Sociedad Europea de Oncología Médica (ESMO), la Sociedad Española de Oncología Médica (SEOM), la Canadian Urological Association (CUA) en colaboración Canadian Uro Oncology Group (CUOG), así como 2 ETS realizadas por The Institute for Quality and Efficiency in Health (IQWIG) y SEOM, y las publicaciones de los resultados finales de dos ECA de fase III (PROSPER para enzalutamida y SPARTAN para apalutamida) que responden a la pregunta PICO. Cabe mencionar que ambos ECA han sido descritos detalladamente en el dictamen previo. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación mantiene la decisión del Dictamen Preliminar de Evaluación de Tecnología Sanitaria N.° 047-SDEPFYOTS-DETS-IETSI-2019, al no contarse con argumentos técnicos que justifiquen la reconsideración del mismo.

Treatment patterns and survival in metastatic castration-sensitive prostate cancer in the US Veterans Health Administration.

BACKGROUND: Limited real-world data exist on treatment patterns and outcomes in patients with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: A retrospective cohort study was conducted, using the Veterans Health Administration claims database (April 2013-March 2018). Among 369,734 prostate cancer patients, we selected all men who developed metastases within 90 days before or after medical/surgical castration and who received androgen deprivation therapy (ADT). Patients were categorized into four cohorts: ADT-only (± <90-day nonsteroidal anti-androgen [NSAA] use), ADT + NSAA, ADT + docetaxel, and ADT + abiraterone. Main outcomes were treatment patterns, time-to-progression to metastatic castration-resistant disease, and overall survival. Multivariable analysis and sensitivity analysis were conducted. RESULTS: Of 1395 patients, 874 (63%) received ADT-only, 338 (24%) received ADT + NSAA, 108 (8%) received ADT + docetaxel, and 75 (5%) received ADT + abiraterone. Proportions on ADT-only and ADT + NSAA declined (from 66% to 60% and from 31% to 17%, respectively) over the study period, while proportions prescribed ADT + docetaxel or abiraterone increased from 3% to 9% and from 1% to 15%, respectively. Patients treated with ADT + NSAA had similar risks of castration-resistant disease (hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.87, 1.26) and overall mortality (HR 1.22; 95% CI: 0.97, 1.54) as ADT-only. CONCLUSIONS: Most patients with mCSPC initiating ADT received ADT-only or ADT + NSAA, despite the emergence of docetaxel and novel hormonal therapies. Even in the most recent period (2017 to early 2018), only 24% of men received intensified therapy with agents known to prolong survival versus ADT-only. These data in real-world clinical practice suggest substantial room for improved outcomes in patients with mCSPC.

A prospective phase-II trial of biweekly docetaxel plus androgen deprivation therapy in patients with previously-untreated metastatic castration-naïve prostate cancer.

INTRODUCTION: The aim of this prospective phase II study was to evaluate the efficacy and safety of biweekly docetaxel plus androgen-deprivation therapy (ADT) in patients with metastatic castration-naïve prostate cancer (mCNPC). PATIENTS AND METHODS: Patients with histologically-proven, previously-untreated mCNPC received ADT plus docetaxel, 40 mg/m2. Docetaxel was repeated every 2 weeks, up to 12 cycles. Endpoints included castration-resistant prostate cancer (CRPC)-free survival, prostate-specific antigen (PSA) response, and safety. RESULTS: A total of 42 patients were registered and analyzed for final outcomes. Of the 42 patients, 36 (86%) completed the 12 planned cycles of docetaxel plus ADT. During a median follow up of 25 months, all but two patients (95%) achieved a PSA response with a nadir PSA level of 0.42 ng/ml (range 0.01-1280.87). The median CRPC-free survival was 26.4 months (95% confidence interval [CI] 20.9-32.0) with a one-year CRPC-free rate of 79% (33 patients, 95% CI 66-91). Multivariable analysis revealed that the performance status of the Eastern Cooperative Oncology Group 0 was independently associated with longer CRPC-free survival (hazard ratio [HR] 0.27, 95% CI 0.07-0.99). The most common adverse events of any grade were anemia (95%), followed by nail changes (33%), fatigue (29%), and oral mucositis (26%). Severe (grade 3 or higher) adverse events were infrequent: pneumonitis (n = 2), diarrhea (n = 1), and neutropenia (n = 1). CONCLUSION: Our results suggest that biweekly docetaxel plus ADT is feasible, and clinical efficacy does not seem to be compromised compared to a standard triweekly docetaxel 75 mg/m2 plus ADT regimen.

Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region.

BACKGROUND: Enzalutamide combined with androgen deprivation therapy (ADT) significantly prolonged metastasis-free survival and overall survival (OS) versus ADT alone in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) with rapidly rising prostate-specific antigen (PSA). The objective of this post hoc analysis of the PROSPER trial is to evaluate OS benefit and safety of enzalutamide in patients across age and regional subgroups. PATIENTS AND METHODS: Eligible men with nmCRPC, PSA doubling time ≤10 months and PSA ≥2 ng/mL with continued ADT use were randomised 2:1 to enzalutamide 160 mg or placebo. OS and safety were examined by age (<70 vs ≥70 years) and region (North America, Europe, Asia or the rest of the world). The impact of prior and subsequent therapy was also examined. RESULTS: In total, 1401 men were enrolled (median age, 74 years). Enzalutamide plus ADT reduced the risk of death, independent of age or region. Multivariate analyses identified Eastern Cooperative Oncology Group (ECOG) status (P < 0.0001), log (PSA; P = 0.0002) and subsequent therapy (P < 0.0001) as statistically significant factors impacting OS. Safety was consistent across age and regional subgroups. Any grade treatment-emergent adverse events were similar across age groups, were more common in the placebo group and had regional variation. CONCLUSIONS: In men with nmCRPC and rapidly rising PSA, the benefit and safety of enzalutamide were consistent across age and regional subgroups. Variables impacting OS included ECOG status, log (PSA) and subsequent therapy. CLINICALTRIALS. GOV IDENTIFIER: NCT02003924.

Spironolactone hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism: in silico studies, statistical optimization, ex vivo, and in vivo studies.

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.