PSA Kinetics Affect Prognosis in Patients With Castration-resistant Prostate Cancer Treated With Enzalutamide.

Background/Aim: There is little evidence regarding the predictive value of prostate-specific antigen (PSA) kinetics in patients with castration-resistant prostate cancer treated with an androgen receptor signaling inhibitor. This study investigated the correlation between PSA kinetics and prognosis in patients with castration-resistant prostate cancer treated with enzalutamide. Patients and Methods: We analyzed data from 103 patients who received enzalutamide as primary treatment for castration-resistant prostate cancer at our hospital, focusing on the associations between overall survival and PSA kinetics variables, such as maximal PSA response, PSA nadir, and time to PSA nadir. Results: The median PSA level at the initiation of enzalutamide was 18.1 ng/ml (interquartile range=7.9-61.2 ng/ml). The median maximal PSA response rate was 88% (interquartile range 55-98), and the median PSA nadir was 1.84 (interquartile range (IQR)=0.38-14.7) ng/ml. The median time to PSA nadir was 19 (IQR=6-28.5) weeks. Maximal PSA response rate <90% [hazard ratio (HR)=2.28, 95% confidence interval (CI)=1.03-5.03, p=0.0413], PSA nadir >2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), time to nadir <19 weeks (HR=2.48, 95%CI=1.15-5.35, p=0.0204) were all independently predictive of shortened overall survival even after adjusting for pre-treatment factors. Conclusion: Maximal PSA response, PSA nadir, and time to PSA nadir correlated with survival in patients with castration-resistant prostate cancer receiving enzalutamide as a first-line therapy.

Falls and fractures in men with prostate cancer taking second-generation androgen receptor antagonists: A retrospective chart review.

INTRODUCTION: Second-generation androgen receptor antagonists, including enzalutamide, apalutamide, and darolutamide, are commonly used to treat metastatic and non-metastatic prostate cancer. Although these medications are typically well-tolerated, falls were reported in 4.2-15.6% of patients and fractures in 4.2-11.7% of patients enrolled in the phase III clinical trials evaluating these drugs in prostate cancer. However, post-marketing studies have reported a lower incidence than reported in clinical trials. The objective of this study is to determine the prevalence of falls and fractures in patients with prostate cancer receiving second-generation androgen receptor antagonists at UConn Health and identify potential risk factors associated with falls and fractures in these patients. METHODS: A retrospective chart review involving patients with prostate cancer treated with darolutamide, enzalutamide, or apalutamide from March 1, 2022, to March 31, 2023, at UConn Health Carole & Ray Neag Comprehensive Cancer Center. Data recorded includes basic demographics, history of fall or fracture, presence of metastases, fall risk, history of osteoporosis, prescribed second-generation androgen receptor antagonist, and other comorbidities. Data was evaluated using descriptive statistics. RESULTS: Twenty-six men were included, all of whom were receiving enzalutamide. At baseline, 96.1% of patients had bone metastases, 15.4% had osteoporosis, 15.4% had osteopenia, and 34.6% had neuropathy. The incidence of falls was 19.2% and the incidence of fractures was 26.9%. The mean length of therapy at time of a fall was 19.44 months (range, 6-31 months). The mean length of therapy at time of a fracture was 19 months (range, 1-33 months). In patients experiencing fall, 100% had arthralgia, 60% had neuropathy, 40% had a gait problem, 40% had hypertension, and 80% of them were at risk of fall. In patients experiencing fracture, 28.6% had osteoporosis, 42.9% had osteopenia, 100% had bone metastases, and 57.1% were on denosumab at time of fracture. CONCLUSION: The prevalence of falls and fractures in patients receiving enzalutamide were higher in this retrospective chart review than reported in clinical trials and post-marketing studies. This could be due to the small patient population or the patient's comorbidities such as osteoporosis, bone metastases, or neuropathy. Fall/fracture risk with enzalutamide and other risk factors for fall and fracture should be considered when discussing treatment and developing a monitoring plan.

Enzalutamide in metastatic hormone-sensitive prostate cancer: A plain language summary of the ARCHES and ENZAMET follow-up studies.

WHAT IS THIS SUMMARY ABOUT?: This summary includes information from the ARCHES and ENZAMET follow-up studies. Both studies looked at enzalutamide treatment for people with metastatic hormone-sensitive prostate cancer (known as mHSPC). In ARCHES, researchers compared the medications enzalutamide + androgen deprivation therapy (known as ADT) with placebo + ADT. In ENZAMET, researchers compared enzalutamide + ADT with standard treatment + ADT. Some people in ENZAMET also took enzalutamide with docetaxel (a chemotherapy treatment). In both studies, researchers wanted to find out if enzalutamide helps people with mHSPC live longer. WHAT ARE THE KEY TAKEAWAYS?: In both studies, researchers found that people with mHSPC who took enzalutamide lived longer than people who did not. People who took enzalutamide also lived longer without their cancer getting worse. The results were mostly similar in groups of people dependingon when and where their cancer was found. Researchers did not find any new safety concerns. WHAT WERE THE MAIN CONCLUSIONS?: People with mHSPC may benefit from long-term treatment with enzalutamide + ADT. They may also benefit from taking enzalutamide with other treatments, like docetaxel. It may be better for people with mHSPC to have enzalutamide treatment before their cancer gets worse, rather than waiting. These people and their doctors should carefully consider the benefits and risks of each treatment to make a joint decision for treating mHSPC.Clinical Trial Registration: NCT02677896 (ARCHES), NCT02446405 (ENZAMET) (ClinicalTrials.gov).

Targeted Delivery of AR-V7 siRNA with Bivalent PSMA Aptamers Effectively Suppresses the Growth of Enzalutamide-Resistant Prostate Cancer.

Androgen deprivation therapy has been the primary treatment strategy for advanced prostate cancer (PCa). But most patients develop castration resistance over time. For FDA-approved second-generation androgen receptor (AR) antagonists, including enzalutamide (ENZ) and abiraterone (AA), patients who initially respond to them eventually develop resistance. The key mechanism for resistance to ENZ/AA involves AR splice variants (AR-Vs) and specifically AR-V7. Current AR antagonists cannot target AR-V7 due to its lack of the C-terminal ligand-binding domain (LBD) but keeping the AR N-terminal domain (NTD) which still can activate androgen-responsive genes. Therefore, targeting the AR NTD and AR-V7 is critically important to overcome ENZ resistance. Unfortunately, AR NTD has been considered an "undruggable" target due to the difficulty in defining its three-dimensional (3D) structure. In this context, siRNA is highly suitable to address this undruggable target. However, siRNA cannot freely diffuse into cells, and a carrier is needed. In this regard, nucleic acid-based aptamers are highly suitable for cell type-specific delivery of siRNA in vivo. In this study, we have developed a serum-stable bivalent prostate-specific membrane antigen (PSMA) aptamer-AR-V7 siRNA chimera (PAP). The results show that PAP can knock down both AR-full length and AR-V7 in PSMA-expressing castration-resistant cells. It can resensitize ENZ in cell lines and PCa xenografts. ENZ combined with PAP can significantly inhibit 22Rv1 xenograft growth in mice without experiencing castration. Owing to the low toxicity, PAP has potential to offer a new antiandrogen treatment for current ENZ-resistant PCa.

Clinical outcomes in metastatic prostate adenocarcinoma treated with abiraterone and enzalutamide.

Aim: The management of metastatic prostate cancer has progressed immensely in the last decade. This study aims to investigate the real-world clinical outcomes of metastatic prostate adenocarcinoma treated with abiraterone and enzalutamide. The findings will assist healthcare providers in making more informed decisions when choosing between these two drugs for treating these patients. Methods: A retrospective analysis of 80 patients at our tertiary care hospital was conducted from January 2015 to July 2022. Data were analysed using SPSS version 20.0. An independent sample T-test was used for continuous data and the chi-square test for categorical data. Medians and means were calculated for continuous or ordinal variables. Kaplan-Meier survival curves presented progression-free and overall survival (OS), with comparisons made using the log-rank test. Survival rates with 95% CIs were reported, with p < 0.05 considered significant. Results: In our final analysis of 80 patients, the median age was 65 years, with 88% having an eastern cooperative oncology group performance status between 0 and 2. Histopathology showed adenocarcinoma in 91% of cases. Grade Group III-IV disease was present in 51.3%, and 67.5% had a Gleason Score of >8. Bilateral orchidectomy was performed in 41 patients (51.25%), with a median Gonadotropin-releasing hormone analogue use of 32 months. Most patients (72.5%) were castration-sensitive. Among the 80 patients, 60 (75%) were treated with abiraterone and 20 (25%) with enzalutamide. The prostate-specific antigen (PSA) doubling time was >6 months in 80% of the abiraterone group and 75% of the enzalutamide group. PSA response rates were similar for both drugs, with comparable rates of progressive disease, partial response, stable disease and complete response (p = 0.036). There was no significant difference in median time to progression (19 months for abiraterone versus 18 months for enzalutamide) (95% CI 9.7-27.9; p = 0.004). The median OS for the entire cohort was 67 months (95% CI 39-94; p = 0.003). Conclusion: The findings suggest that both abiraterone and enzalutamide are effective in prolonging progression-free and overall survival in this patient population, providing comparable safety. Further studies are recommended to validate these findings and inform clinical decision-making.

Docetaxel Versus Androgen-Receptor Signaling Inhibitors (ARSI) as Second-Line Therapy After Failure of First-Line Alternative ARSI for the Elderly ≥ 75 Years Old With Metastatic Castration-Resistant Prostate Cancer (mCRPC): A SPARTACUSS-Meet-URO 26 Real-World Study.

BACKGROUND: Androgen receptor signalling inhibitors (ARSIs) abiraterone acetate (AA) enzalutamide (Enza), are currently the standard first-line (L1) treatments for metastatic castration-resistant prostate cancer (mCRPC), and docetaxel (D) is reserved as second-line (L2) after ARSI failure. Nonetheless, D use in men ≥ 75 years old is restricted owing to treatment toxicities and patient comorbidities, and a L2 alternative ARSI is frequently used. We aimed to evaluate real-life survival and toxicity outcomes of these elderly patients after failure of L1 ARSI treatment. MATERIAL AND METHODS: We retrospectively evaluated efficacy and safety in a real-world international cohort of consecutive patients ≥ 75 years old when starting L1 ARSI for mCRPC according to the choice of L2 treatment (D versus alternative ARSI). RESULTS: Of the 122 identified patients, 57 (46.7%) had received L2 ARSI and 65 (53.3%) L2 D. No difference was found in the L1 overall survival (OS) for the ARSI and D groups (32.8 vs. 30.0 months, respectively; Hazard ratio [HR] = 1.22; 95% CI, 0.77-1.95; P = .40) or in the L2 OS (18.5 vs. 17.8 months, respectively; HR = 1.09; 95% CI, 0.69-1.74; P = .71). No difference was observed for rPFS from L2 (P = .12), although a trend was observed for a numerically improved rPFS on D. CONCLUSION: Within the limitations of a retrospective design and small population, our study suggests that D or ARSI after failure of L1 alternative ARSI are clinically comparable L2 options for elderly patients with mCRPC.

Enzalutamide versus abiraterone acetate in the development of new-onset or worsening type 2 diabetes mellitus in patients with metastatic castration-resistant prostate cancer: EVADE study.

PURPOSE: To determine new-onset or worsening T2DM risk in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone acetate (AA) vs. enzalutamide (ENZA) in England. METHODS: Records of patients on AA and/or ENZA (2015-2021) were analysed retrospectively from UK- or England-wide databases and data sets. The primary endpoint was new-onset or worsening T2DM, analysed using a Cox model. RESULTS: Of 1382 patients, 84 (6.1%) met the primary endpoint; 42 of 826 patients (5.1%) received ENZA and 42 of 556 patients (7.6%) received AA. Among patients without baseline T2DM (n = 1049), 50 developed new-onset T2DM: 24 (3.9%) on ENZA and 26 (5.9%) on AA. Among patients with baseline T2DM (n = 333), 34 (10.2%) had worsening T2DM: 18 (8.3%) on ENZA and 16 (13.8%) on AA. Patients on ENZA had longer median follow-up (445 vs. 408 days) and treatment duration (164 vs. 139 days) than those on AA, who were also more likely to have new-onset or worsening T2DM than those on ENZA (HR: 1.8; 95% CI: 1.4-2.7; P = 0.0101). The number needed to harm for an additional patient to experience new-onset or worsening T2DM when receiving AA instead of ENZA was 40 overall, 50 in patients without baseline T2DM, and 18 in patients with baseline T2DM. CONCLUSION: Patients with mCRPC receiving AA were more likely to experience new-onset or worsening T2DM than those on ENZA, despite having a shorter treatment duration. Further research is required to substantiate these findings in earlier disease settings with longer treatment duration.

The prognostic superiority of second-generation androgen receptor signaling inhibitor in patients with non-metastatic castration-resistant prostate cancer.

OBJECTIVE: The aim of this study was to compare prognostic outcomes of administering first- or second-generation androgen receptor signaling inhibitors in non-metastatic castration-resistant prostate cancer and to find prognostic indicators. METHODS: This retrospective study included 198 patients with non-metastatic castration-resistant prostate cancer from 14 institutions associated with Tokai Urologic Oncology Research Seminar. Forty-two patients were treated with combined androgen blockade using first-generation inhibitors (bicalutamide or flutamide), and 156 were treated with second-generation inhibitors (abiraterone/enzalutamide or apalutamide/darolutamide) after primary androgen deprivation therapy failure. We compared survival outcomes of combined androgen blockade using first-generation inhibitors and second-generation inhibitor treatments, and analyzed clinicopathological or serum parameters and survival outcome. RESULTS: Combined androgen blockade and second-generation androgen receptor signaling inhibitor groups demonstrated median progression-free survival of 10.2 (95% confidence interval: 5.5-12.3) and 26.0 (95% confidence interval: 21.9-38.4; P < 0.001) months, respectively. Cut-off levels for clinical biomarkers were targeted to <0.2 ng/ml prostate-specific antigen levels 3 months after treatment initiation for non-metastatic castration-resistant prostate cancer; the patient group that achieved this showed better progression-free survival (median 14.7 months, 95% confidence interval: 10.3-23.9 not achieved, median not applicable, 95% confidence interval: 24.6-not applicable achieved; P < 0.00001). Multivariate analysis revealed significant prognostic factors: second-generation androgen receptor signaling inhibitor as first-line treatment (odds ratio: 5.05, 95% confidence interval: 1.54-16.6) and a high hemoglobin level (odds ratio: 2.92, 95% confidence interval: 1.26-6.76). CONCLUSIONS: Our findings suggested prostate-specific antigen < 0.2 ng/ml after 3 months may be a practical prognostic indicator of survival outcomes in non-metastatic castration-resistant prostate cancer. Patients showing a high hemoglobin level should be intensively treated with second-generation androgen receptor signaling inhibitors rather than combined androgen blockade using first-generation inhibitors.

Phase II clinical trial assessing the efficacy of enzalutamide in advanced non-resectable granulosa cell ovarian tumors: The GREKO III study (GETHI2016-01).

BACKGROUND: Granulosa cell ovarian tumors (GCT) are orphan disease with limited treatments. Hormone therapy is a potential treatment, due to the overexpression of hormone receptors in most tumors. This study explores the activity of the antiandrogen, enzalutamide, in metastatic cases. METHODS: We designed a phase II clinical trial under the Spanish Collaborative Group for Transversal Oncology and Rare and Orphan Tumors (GETTHI). Eligible participants were adult women with advanced GCT. Primary endpoint was objective response rate. Secondary endpoints included clinical benefit rate, progression-free survival, overall survival, and safety profile. Patients received enzalutamide 160 mg once daily. RESULTS: From April 2018 to March 2020, eighteen patients were screened, and sixteen were included across nine institutions. Median age was 56.4 years (range 45-71), and most were Caucasian (14 cases), one Arabian and one Latin. ECOG performance status was zero in 13 cases (81 %) and one in three (19 %). Six patients (38 %) had previously received hormone therapy as adjuvant treatment or for advanced disease, and 15 (94 %) chemotherapy. Median time from metastasis to study entry was 96 months (range 4.5-198). No objective response was observed, but the clinical benefit rate reached 68.8 % (95 % CI [46 %-91.5 %]). Median progression-free survival was 3.8 months (95 % CI [1.36-6.14]). Median overall survival was not reached, with a median follow-up of 6 months (range 2.2-19). At the time of database closure, 14 patients had discontinued treatment, 13 due to disease progression and one by personal choice. Two deaths attributed to disease progression were recorded. Five grade 3 adverse events were reported, with only one (asthenia) deemed related to the therapy. CONCLUSIONS: Although enzalutamide demonstrated modest activity in GCT, durable stabilization was observed in some cases. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03464201.

Predicting time to castration resistance with androgen-receptor signaling inhibitors in hormone-sensitive prostate cancer: data from ULTRA-Japan Consortium.

BACKGROUND: Androgen-receptor signaling inhibitors (ARSIs) become the new standard of care for metastatic hormone-sensitive prostate cancer (mHSPC). It is unknown whether time to castration resistance (TTCR), when using the first-line ARSIs, offers predictive value in mHSPC. We sought to assess the clinical outcomes for mHSPC patients treated with first-line ARSIs focusing on the TTCR. METHODS: Data from the ULTRA-Japan study cohort from five academic institutes (496 mHSPC patients) were retrospectively analyzed. RESULTS: The median overall survival (OS) in the total cohort was 80 months with a median follow-up of 18 months. Of 496 patients, 332 (67%), 82 (16.5%), and 82 (16.5%) were treated with first-line abiraterone acetate + prednisone, enzalutamide, and apalutamide, respectively. During the follow-up, a total of 155 (31%) were diagnosed with mCRPC with a median TTCR of 10 months. In those 155 patients, TTCR > 12 months is an independent predictor of longer OS from the first-line ARSIs. Cox regression analysis of the TTCR from initiating first-line ARSI in 496 mHSPC patients revealed three variables as independent predictors of shorter TTCR, including Gleason's score (GS) ≥ 9, the extent of disease (EOD) ≥ 2, and the presence of liver metastasis. CONCLUSION: Our results indicate that mHSPC patients with those three features are likely to have primary resistance to first-line ARSIs (doublet therapy), thus requiring consideration of other options, such as the recent triplet approach.

MYO6 contributes to tumor progression and enzalutamide resistance in castration-resistant prostate cancer by activating the focal adhesion signaling pathway.

BACKGROUND: Enzalutamide (Enz) resistance is a poor prognostic factor for patients with castration-resistant prostate cancer (CRPC), which often involves aberrant expression of the androgen receptor (AR). Myosin VI (MYO6), one member of the myosin family, plays an important role in regulating cell survival and is highly expressed in prostate cancer (PCa). However, whether MYO6 is involved in Enz resistance in CRPC and its mechanism remain unclear. METHODS: Multiple open-access databases were utilized to examine the relationship between MYO6 expression and PCa progression, and to screen differentially expressed genes (DEGs) and potential signaling pathways associated with the MYO6-regulated Enz resistance. Both in vitro and in vivo tumorigenesis assays were employed to examine the impact of MYO6 on the growth and Enz resistance of PCa cells. Human PCa tissues and related clinical biochemical data were utilized to identify the role of MYO6 in promoting PCa progression and Enz resistance. The molecular mechanisms underlying the regulation of gene expression, PCa progression, and Enz resistance in CRPC by MYO6 were investigated. RESULTS: MYO6 expression increases in patients with PCa and is positively correlated with AR expression in PCa cell lines and tissues. Overexpression of AR increases MYO6 expression to promote PCa cell proliferation, migration and invasion, and to inhibit PCa cell apoptosis; whereas knockdown of MYO6 expression reverses these outcomes and enhances Enz function in suppressing the proliferation of the Enz- sensitive and resistant PCa cells both in vitro and in vivo. Mechanistically, AR binds directly to the promoter region (residues - 503 to - 283 base pairs) of MYO6 gene and promotes its transcription. Furthermore, MYO6 activates focal adhesion kinase (FAK) phosphorylation at tyrosine-397 through integrin beta 8 (ITGB8) modulation to promote PCa progression and Enz resistance. Notably, inhibition of FAK activity by Y15, an inhibitor of FAK, can resensitize CRPC cells to Enz treatment in cell lines and mouse xenograft models. CONCLUSIONS: MYO6 has pro-tumor and Enz-resistant effects in CRPC, suggesting that targeting MYO6 may be beneficial for ENZ-resistant CRPC therapy through the AR/MYO6/FAK signaling pathway.

Androgen receptor pathway inhibitors and drug-drug interactions in prostate cancer.

Prostate cancer represents a major global health challenge, necessitating efficacious therapeutic strategies. Androgen receptor pathway inhibitors (ARPIs) have become central to prostate cancer treatment, demonstrating significant effectiveness in both metastatic and non-metastatic contexts. Abiraterone acetate, by inhibiting androgen synthesis, deprives cancer cells androgens necessary for growth, while second-generation androgen receptor (AR) antagonists disrupt AR signaling by blocking AR binding, thereby impeding tumor progression. Given the predominance of prostate cancer in the elderly, who often present with multiple comorbidities requiring complex pharmacological regimens, the potential for drug-drug interactions with ARPIs is a critical concern. These interactions, particularly through pathways like CYP2D6 inhibition by abiraterone and CYP3A4 induction by enzalutamide and apalutamide, necessitate a thorough understanding to optimize therapeutic outcomes and minimize adverse effects. This review aims to delineate the efficacy of ARPIs in prostate cancer management and elucidate their interaction with common medications, highlighting the importance of vigilant drug management to optimize patient care.

Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma.

Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between androgen receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and in vivo. Mechanistically, we demonstrated that intracellular reactive oxygen species (ROS) function as upstream mediators of apoptosis and ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 00, 000-000.

Relugolix Plus Enzalutamide For Metastatic Hormone-Sensitive Prostate Cancer: A Case Report.

Background: In the UK, relugolix, an oral gonadotropin-releasing hormone receptor antagonist, is indicated for advanced hormone-sensitive prostate cancer, and as neo-adjuvant and adjuvant treatment in combination with radiotherapy in patients with high-risk localised or locally advanced hormone-dependent prostate cancer. Experience with the combination of oral relugolix plus oral enzalutamide is limited. Case Presentation: A white British male (66 years old) with a history of myelodysplastic syndrome, chronic neutropenia and indeterminate colitis presented with metastatic adenocarcinoma of the prostate gland. The patient started subcutaneous leuprorelin acetate and oral enzalutamide. After 8 weeks, the oral enzalutamide dose was reduced because of fatigue. Following the second leuprorelin injection, the patient developed a subcutaneous abscess that required surgical incision and drainage. The patient switched to oral relugolix and continued with oral enzalutamide. Within 3 months of commencing leuprorelin and enzalutamide the prostate specific antigen (PSA) concentration fell from a peak of 269.00 ng/mL to 2.55 ng/mL. Following the switch to oral relugolix plus enzalutamide, the PSA remained stable until the most recent assessment 11 months later. Relugolix plus enzalutamide was well tolerated. Conclusion: Relugolix plus enzalutamide produced a sustained reduction in PSA and the combination was well tolerated. Further research including real world data should assess relugolix in doublet and triplet combinations for prostate cancer.

Oral (by mouth) relugolix can treat certain men with hormone sensitive prostate cancer. Studies are underway looking at relugolix combined with other drugs, such as oral enzalutamide, and at various stages of prostate cancer. Dr Thomson et al report the case of a man with other serious diseases who took oral relugolix and oral enzalutamide after experiencing side effects with injectable drugs. His levels of prostate specific antigen (PSA), which indicates prostate cancer control (the lower the better), fell markedly after starting treatment and, after switching to relugolix, remained stable for 11 months. He tolerated relugolix plus enzalutamide well.

Comparison of abiraterone, enzalutamide, and apalutamide for metastatic hormone-sensitive prostate cancer: A multicenter study.

PURPOSE: We aimed to assess the differential efficacy and safety of androgen receptor pathway inhibitors (ARPI), such as abiraterone, enzalutamide, and apalutamide, in patients with metastatic hormone-sensitive prostate cancer (mHSPC) in a real-world practice setting. METHODS: We retrospectively reviewed the records of consequent 668 patients with mHSPC treated with ARPI plus androgen deprivation therapy between September 2015 and December 2023. Based on the LATITUDE criteria, the comparison among abiraterone, enzalutamide, and apalutamide was exclusively conducted in high-risk patients. Prostate-specific antigen (PSA) responses such as the achievement of 95% and 99% PSA decline, overall survival (OS), cancer-specific survival (CSS), time to castration-resistant prostate cancer (CRPC), and the incidence of adverse events (AEs) were compared. All two-group comparisons relied on propensity score matching (PSM) to minimize the effect on possible confounders. RESULTS: In total, 297 patients with high-risk mHSPC treated with abiraterone, 127 with enzalutamide, and 142 with apalutamide were compared. There were no differences in time to CRPC (p = 0.13), OS (p = 0.7), and CSS (p = 0.5) among the three ARPIs. No differences were observed in the achievement rates for 95% PSA decline at 3 months among the three ARPIs, while abiraterone was significantly better in 99% PSA decline achievement compared to apalutamide (72% vs. 57%, p = 0.003). The aforementioned oncologic outcomes were sustained even when performing PSM analyzes. Although skin rash for APA (34%) was the highest incidence of AEs, there were no differences in the rates of severe AEs across the three ARPIs. Enzalutamide resulted in the lowest treatment discontinuation rates (10%) other than disease progression compared to the other regimens. CONCLUSIONS: Abiraterone, enzalutamide, and apalutamide have comparable oncologic outcomes in terms of OS, CSS, and time to CRPC in patients with high-risk mHSPC. Our data on differential treatment discontinuation rates, PSA response, and AE profiles can help guide clinical decision-making.

18ß-Glycyrrhetinic acid synergizes with enzalutamide to counteract castration-resistant prostate cancer by inhibiting OATP2B1 uptake of dehydroepiandrosterone sulfate.

Androgen dependence is a key feature of prostate cancer, and androgen deprivation is effective in treating prostate cancer. However, the disease often worsens and develops into castration-resistant prostate cancer after short-term control. The current study aimed to explore the mechanism of the synergistic action of 18ß-glycyrrhetinic acid (18ß-GA) and enzalutamide (ENZ) against prostate cancer. Our findings showed that 18ß-GA significantly inhibited the expression of OATP2B1 and the transport of dehydroepiandrosterone sulfate (DHEAS) in LNCap and 22RV1 cells. It also downregulated the expression of androgen receptor (AR) to some extent. ENZ strongly inhibited AR expression, but it did not affect OATP2B1-mediated uptake of DHEAS. Compared to the effects of 18ß-GA and ENZ alone, the combination of 18ß-GA and ENZ significantly enhanced the inhibitory effects on AR, prostate-specific antigen (PSA) expression, tumor cell proliferation, and migration. The results obtained in castrated model mice matched the findings of in vitro experiments. 18ß-GA significantly reduced the uptake of DHEAS mediated by OATP2B1 in mouse tumor tissues and cooperated with ENZ to further inhibit the expression of AR and PSA, combat the growth of tumor cells, and promote the apoptosis of tumor cells. In conclusion, 18ß-GA considerably decreased the uptake of DHEAS and androgen production in cells by inhibiting the transport function of OATP2B1, while ENZ inhibited the nuclear translocation of AR and reduced the expression of AR. The combination of 18ß-GA and ENZ can simultaneously inhibit androgen production and AR expression and exhibit a synergistic effect against castration and prostate cancer progression.

Talazoparib Plus Enzalutamide in Patients With HRR-Deficient mCRPC: Practical Implementation Steps for Oncology Nurses and Advanced Practice Providers.

BACKGROUND: About one-quarter of patients with advanced prostate cancer have alterations in homologous recombination repair (HRR) genes. In a global phase 3 study, talazoparib plus enzalutamide significantly improved progression-free survival in patients with HRR-deficient metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVES: This article reviews the role of oncology nurses and advanced practice providers (APPs) in administering talazoparib plus enzalutamide in patients with mCRPC. METHODS: This review and hypothetical case study illustrate the role of oncology nurses and APPs in the administration of talazoparib plus enzalutamide and the management of adverse events to ensure safe and effective use in clinical practice. FINDINGS: Oncology nurses and APPs play an important role in the dosing and administration of talazoparib plus enzalutamide and can recognize and manage adverse events in patients with HRR-deficient mCRPC.

Connecting Gene Variation to Treatment Outcomes in Metastatic Castration-Resistant Prostate Adenocarcinoma: Insights into Second-Generation Androgen Receptor Axis-Targeted Therapies.

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment.

Human intermediate prostate cancer stem cells contribute to the initiation and development of prostate adenocarcinoma.

BACKGROUND: Intermediate cells are present in the early stages of human prostate development and adenocarcinoma. While primary cells isolated from benign human prostate tissues or tumors exhibit an intermediate phenotype in vitro, they cannot form tumors in vivo unless genetically modified. It is unclear about the stem cell properties and tumorigenicity of intermediate cells. METHODS: We developed a customized medium to culture primary human intermediate prostate cells, which were transplanted into male immunodeficient NCG mice to examine tumorigenicity in vivo. We treated the cells with different concentrations of dihydrotestosterone (DHT) and enzalutamide in vitro and surgically castrated the mice after cell transplantation in vivo. Immunostaining, qRT-PCR, RNA sequencing, and western blotting were performed to characterize the cells in tissues and 2D and 3D cultures. RESULTS: We found intermediate cells expressing AR+PSA+CK8+CK5+ in the luminal compartment of human prostate adenocarcinoma by immunostaining. We cultured the primary intermediate cells in vitro, which expressed luminal (AR+PSA+CK8+CK18+), basal (CK5+P63+), intermediate (IVL+), and stem cell (CK4+CK13+PSCA+SOX2+) markers. These cells resisted castration in vitro by upregulating the expression of AR, PSA, and proliferation markers KI67 and PCNA. The intermediate cells had high tumorigenicity in vivo, forming tumors in immunodeficient NCG mice in a month without any genetic modification or co-transplantation with embryonic urogenital sinus mesenchyme (UGSM) cells. We named these cells human castration-resistant intermediate prostate cancer stem cells or CriPCSCs and defined the xenograft model as patient primary cell-derived xenograft (PrDX). Human CriPCSCs resisted castration in vitro and in vivo by upregulating AR expression. Furthermore, human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in PrDX tumors in vivo, which can dedifferentiate into CriPCSCs in vitro. CONCLUSIONS: Our study identified and established methods for culturing human CriPCSCs, which had high tumorigenicity in vivo without any genetic modification or UGSM co-transplantation. Human CriPCSCs differentiated into amplifying adenocarcinoma cells of luminal phenotype in the fast-growing tumors in vivo, which hold the potential to dedifferentiate into intermediate stem cells. These cells resisted castration by upregulating AR expression. The human CriPCSC and PrDX methods hold significant potential for advancing prostate cancer research and precision medicine.

Sialylation Inhibition Can Partially Revert Acquired Resistance to Enzalutamide in Prostate Cancer Cells.

Prostate cancer is a lethal solid malignancy and a leading cause of cancer-related deaths in males worldwide. Treatments, including radical prostatectomy, radiotherapy, and hormone therapy, are available and have improved patient survival; however, recurrence remains a huge clinical challenge. Enzalutamide is a second-generation androgen receptor antagonist that is used to treat castrate-resistant prostate cancer. Among patients who initially respond to enzalutamide, virtually all acquire secondary resistance, and an improved understanding of the mechanisms involved is urgently needed. Aberrant glycosylation, and, in particular, alterations to sialylated glycans, have been reported as mediators of therapy resistance in cancer, but a link between tumour-associated glycans and resistance to therapy in prostate cancer has not yet been investigated. Here, using cell line models, we show that prostate cancer cells with acquired resistance to enzalutamide therapy have an upregulation of the sialyltransferase ST6 beta-galactoside alpha-2,6-sialyltransferase 1 (ST6GAL1) and increased levels of α2,6-sialylated N-glycans. Furthermore, using the sialyltransferase inhibitor P-SiaFNEtoc, we discover that acquired resistance to enzalutamide can be partially reversed by combining enzalutamide therapy with sialic acid blockade. Our findings identify a potential role for ST6GAL1-mediated aberrant sialylation in acquired resistance to enzalutamide therapy for prostate cancer and suggest that sialic acid blockade in combination with enzalutamide may represent a novel therapeutic approach in patients with advanced disease. Our study also highlights the potential to bridge the fields of cancer biology and glycobiology to develop novel combination therapies for prostate cancer.