Prostate cancer (PC) is generally a hormone-dependent tumor. Androgen deprivation therapy ( has been the standard of care in metastatic disease for more than 80 years. Subsequent studies have highlighted the efficacy of ADT even in earlier disease settings such as in localized disease or in the case of biochemical recurrence (BCR). Improved knowledge of PC biology and ADT resistance mechanisms have led to the development of novel generation androgen receptor pathway inhibitors (ARPI). Initially used only in patients who became resistant to ADT, ARPI have subsequently shown to be effective when used in patients with metastatic hormone-naive disease and in recent years their effectiveness has also been evaluated in localized disease and in case of BCR. The objective of this review is to describe the current role of agents interfering with the androgen receptor in different stages of PC and to point out future perspectives.

The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.

BACKGROUND: We previously reported that for men undergoing combined androgen deprivation therapy (ADT) and radiation therapy (RT) for prostate cancer, substitution of LHRH-agonists with 5-α- reductase inhibitors (5-ARIs) led to improved preservation of 6-month hormonal quality of life (hQOL). With longer term follow-up, we evaluated disease control.
METHODS: In this non-randomized trial, men with unfavorable intermediate or high-risk prostate cancer, aged ≥70 years or with Charlson Comorbidity Index ≥2, were treated with RT (78-79.2 Gy in 39-44 fractions) and either oral ADT (oADT; 5-ARI with antiandrogen) or standard of care ADT (SOC; leuprolide with antiandrogen) for up to 28 months. The primary endpoint was EPIC hQOL; secondary endpoints included biochemical control and survival as well as changes in cholesterol and hemoglobin levels.
RESULTS: Between 2011 and 2018, 70 men were enrolled (40 in oADT; 30 in SOC). Median follow-up was 65 months [IQR 36-94]. Five-year freedom from biochemical failure for oADT and SOC was 89% versus 86%, disease free survival was 62% versus 69%, cancer-specific survival was 100% versus 96%, and overall survival was 70% versus 81% (all P>.1). Testosterone (2 mo through 3 yr) and hemoglobin levels (2 mo through 2 yr) were higher, and cholesterol levels (1 yr) were lower in the oADT groups (all P < .05).
CONCLUSIONS: In this non-randomized study, men treated with combined RT and oADT had better preservation of hQOL and comparable 5-year disease outcomes to men treated with SOC. Eugonadal testosterone with this approach may yield measurable benefits in cholesterol and hemoglobin levels.

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UNASSIGNED: The current treatment strategy for metastatic Hormone-Sensitive Prostate Cancer (mHSPC) is the combination of Androgen Receptor Signaling Inhibitors (ARSIs) medicines with androgen deprivation therapy (ADT). However, there is a lack of real-world data comparing the efficacy of different ARSI pharmaceuticals. Therefore, the objective of this study was to compare the effectiveness and safety of bicalutamide, abiraterone, enzalutamide, and apalutamide in combination with ADT for patients with mHSPC.
UNASSIGNED: We retrospectively analyzed 82 patients diagnosed with mHSPC, including 18 patients treated with abiraterone acetate with prednisone, 21 patients with enzalutamide, 20 patients with apalutamide, and 23 patients with bicalutamide. We evaluated PSA progression-free survival (PSA-PFS), imaging progression-free survival (r PFS), castration resistance progression-free survival (CRPC-PFS), and overall survival (OS) using Kaplan-Meier survival analyses. Additionally, we explored relevant factors affecting prognosis through univariate and multivariate Cox risk-proportionality models. PSA response rates at 3, 6, and 12 months, nadir PSA levels (nPSA), and time to nadir (TTN) in different medication subgroups after treatment were documented, and we used one-way ANOVA to determine the effect of these measures on patient prognosis.
UNASSIGNED: In comparison with bicalutamide, both enzalutamide and apalutamide have shown significant advantages in delaying disease progression among mHSPC patients. Specifically, enzalutamide has been found to significantly prolong PSA-PFS (HR 2.244; 95% CI 1.366-3.685, p=0.001), rPFS (HR 2.539; 95% CI 1.181-5.461; p= 0.007), CRPC-PFS (HR 2.131; 95% CI 1.295-3.506; p= 0.003), and OS (HR 2.06; 95% CI 1.183-3.585; P=0.005). Similarly, apalutamide has significantly extended PSA-PFS (HR 5.071; 95% CI 1.711-15.032; P= 0.003) and CRPC-PFS (HR 6.724; 95% CI 1.976-22.878; P=0.002) among patients. On the other hand, the use of abiraterone in combination with ADT did not demonstrate a significant advantage in delaying diseases progression when compared with the other three agents in mHSPC patients. There were no significant differences in overall adverse event rates among the four pharmaceuticals in terms of safety. Additionally, the observation of PSA kinetics revealed that enzalutamide, apalutamide, and abiraterone acetate had a significant advantage in achieving deep PSA response (PSA ≤ 0.2 ng/ml) compared with bicalutamide (p=0.007 at 12 months). Enzalutamide and apalutamide exhibited preeminence efficacy, with no substantial difference observed between the two medications.
UNASSIGNED: Abiraterone, enzalutamide, and apalutamide were found to significantly reduce and stabilize PSA levels in mHSPC patients more quickly and thoroughly than bicalutamide. Furthermore, enzalutamide and apalutamide were found to significantly prolong survival and delay disease progression in mHSPC patients compared with bicalutamide. It should be noted that abiraterone did not demonstrate a significant advantage in delaying disease compared with enzalutamide and apalutamide. After conducting drug toxicity analyses, it was determined that there were no significant differences among the four drugs.

UNASSIGNED: Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT).
UNASSIGNED: Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage.
UNASSIGNED: The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother.
UNASSIGNED: In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.

UNASSIGNED: The Prostate Imaging for Recurrence Reporting (PI-RR) system was recently proposed to assess the local recurrence of prostate cancer (PCa), but its exact performance for the prostate after radiotherapy or radical prostatectomy is difficult to determine. We aimed to evaluate the diagnostic performance and interreader agreement of this system using whole-mount histology of the prostate after androgen deprivation therapy (ADT) as the standard of reference.
UNASSIGNED: In total, 119 patients with PCa post-ADT underwent multiparametric magnetic resonance imaging (mp-MRI) before prostatectomy. Three radiologists analyzed the MRI images independently, scoring imaging findings according to PI-RR. Spearman correlation was performed to assess the relationship between the percentage of sectors with residual cancer and PI-RR score. The diagnostic performance for detection of residual cancer was assessed on a per-sector basis. The chi-squared test was used to compare the cancer detection rate (CDR) among readers. Overall and pairwise interreader agreement in assigning PI-RR categories and residual cancer sectors with a score ≥3 or ≥4 were evaluated with the Cohen kappa coefficient.
UNASSIGNED: Histology revealed 209 sectors with residual cancer. The percentage of pathologically positive sectors increased with the increase in PI-RR score for all readers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) at a cutoff of score 3 ranged from 74.2% to 83.7%, 86.4% to 92.7%, 51.3% to 64.3%, and 95.4% to 96.9%, respectively, and at a cutoff of score 4, they ranged from 47.4% to 56.5%, 97.9% to 98.6%, 82.5% to 85.3%, and 91.6% to 92.9%, respectively. There was no significant difference among the CDR of readers. In PI-RR categories and detection of residual cancer sectors, overall interreader agreement was moderate for all readers, but agreement was higher between the more experienced readers (moderate to substantial) than between the more and less experienced readers (fair to moderate).
UNASSIGNED: MRI scoring with the PI-RR assessment provided accurate evaluation of PCa after ADT, but readers\' experience influenced interreader agreement and cancer diagnosis.

UNASSIGNED: Prostate cancer represents a major health concern worldwide, with the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and locally advanced prostate cancer posing a particular challenge. Rezvilutamide, a new androgen receptor antagonist from China, has shown early promise; however, its real-world effectiveness and safety profile require further evidence. This case series evaluates the preliminary clinical outcomes of rezvilutamide in combination with androgen deprivation therapy (ADT), focusing on PSA response and radiological findings across various stages of prostate cancer in four patients.
UNASSIGNED: Case 1 details a 68-year-old male with low-volume mHSPC who exhibited a positive therapeutic response, demonstrated by decreasing PSA levels and improved radiographic results, despite experiencing mild side effects related to the drug. Case 2 describes a 71-year-old male with high-volume mHSPC who had a favorable outcome, with no significant changes in tumor size or metastatic spread and no negative reactions to the drug. Case 3 involves a 55-year-old male with locally advanced prostate cancer, who saw a reduction in PSA levels and a small decrease in tumor volume, yet with ongoing bladder involvement. Genetic testing showed no significant mutations. Case 4 presents a 74-year-old male with extensive metastatic disease who initially responded to the treatment but later exhibited disease advancement and an ATM gene mutation, signaling a shift to metastatic castration-resistant prostate cancer (mCRPC). This finding underscores the crucial role of genetic testing in directing future treatment, with therapies such as olaparib or chemotherapy being advised.
UNASSIGNED: Rezvilutamide has shown a potential benefit in the management of mHSPC and locally advanced prostate cancer, generally with a mild safety profile. Initial positive responses, particularly in PSA decline and radiographic progression, are promising. Nevertheless, the varying responses, notably concerning genetic mutations, highlight the necessity for tailored treatment approaches. Due to the small cohort and brief follow-up period, more extensive research with larger populations and prolonged monitoring is essential to conclusively determine the benefits and safety of rezvilutamide. The utilization of genetic insights is key to refining treatment decisions and enhancing outcomes for patients with advanced prostate cancer.

BACKGROUND: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity.
METHODS: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS).
RESULTS: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively.
CONCLUSIONS: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

To analyze potential racial disparities in the diagnosis and management of depression associated with androgen deprivation therapy.
TriNetX health record network was queried for prostate cancer patients treated with androgen deprivation therapy from 2003-2023. Differences in rates of depression diagnosis and treatment were compared between White and Black patients. Means, odds ratios, and t tests were calculated in univariate analysis with 95% confidence intervals (CI).
Data were queried from 93 health care organizations to yield 78,313 prostate cancer patients treated with androgen deprivation therapy. Patients on androgen deprivation therapy had 60% greater odds of developing depression vs other patients [9% vs 6%; odds ratio (OR) 1.6; 95% CI (1.5-1.7); P <.0001]. Of those with depression secondary to androgen deprivation therapy, only 35% were treated with antidepressants. After starting androgen deprivation therapy, White patients had 30% greater odds of being diagnosed with depression, compared to Black patients [10% vs 8%; OR 1.3; 95% CI (1.2-1.4); P <.001]. White patients also had higher odds of being treated with a first line antidepressant than Black patients [56% vs 48%; OR 1.4, 95% CI (1.2-1.6), P <.001].
This analysis confirms a significant association between androgen deprivation therapy and the development of clinical depression, and highlights its medical undertreatment. Importantly, our findings also indicate significant racial disparities in the identification and treatment of depression. Routine screening initiatives that account for social determinants of health may alleviate this disparity. Limitations of this study include retrospective design and lack of data describing severity of depression, which might correlate with need for medication.