Search Results (46)

Accurate measurement of androgen receptor pathway inhibitors (ARPIs) and their active metabolites is essential for pharmacokinetic studies and therapeutic drug monitoring (TDM) in patients with prostate cancer (PC). However, their simultaneous determination in human plasma is analytically challenging because of the wide concentration ranges. This study aimed to develop and validate a sensitive and robust LC–MS/MS method for the quantification of abiraterone, Δ4-abiraterone, enzalutamide, N-desmethyl enzalutamide, darolutamide, keto-darolutamide, apalutamide, and N-desmethyl apalutamide in human plasma. Sample preparation was performed by protein precipitation, followed by chromatographic separation and detection using multiple reaction monitoring with isotopically labeled internal standards (total run time 6.5 min). The method was validated in accordance with regulatory guidelines by assessing selectivity, linearity, sensitivity, accuracy, precision, recovery, matrix effects, and stability. The assay demonstrated good linearity (≥0.997) across clinically relevant concentration ranges, with lower limits of quantification between 0.1 and 40 ng/mL, depending on the analyte. Intra- and inter-day precision and accuracy were within acceptable limits, and recovery and matrix effects were consistent across different plasma matrices. Stability experiments conducted in plasma and whole blood provided practical guidance for sample handling. The method was successfully applied to 79 plasma samples from 61 patients with metastatic PC. Measured concentrations were generally consistent with published pharmacokinetic data, while unexpectedly high ABI levels were observed. Sample collection occurred between 1 and 28 h after the last drug intake, enabling assessment of the analytical method across the entire pharmacokinetic profile. Full article

Androgen receptor (AR) signaling is crucial for mediating male-typical behaviors across vertebrates. Enzalutamide (ENZ) and apalutamide (APA) are two second-generation androgen receptor inhibitors (SGARIs) that have been primarily used in the treatment of prostate cancer. However, these drugs still possess side effects, and there remains limited information regarding their behavioral and neurophysiological impacts following chronic exposure in non-mammalian animal models, particularly in fish. Thus, this study aimed to evaluate the behavioral alterations in adult male zebrafish (Danio rerio) following exposure to specific AR blockers (ENZ and APA) and an activator, dihydrotestosterone (DHT), to provide a comprehensive comparison between each tested drug. Adult male zebrafish were exposed via aqueous immersion to each compound at a 1 ppm concentration for ~2 weeks and were subjected to a battery of behavioral tests. From the results, both AR blockers were found to slightly compromise fish locomotion, with contrary results observed in DHT-treated fish, which displayed an increased locomotor activity together with slight alterations in fish exploratory behaviors. Furthermore, ENZ also caused a tightened shoal formation in zebrafish, while exposure to APA was observed to slightly diminish the fear response of fish. On the other hand, the DHT-treated group displayed a higher level of aggression compared to the vehicle control group. In conclusion, functional modulation of androgen receptor signaling leads to significant alterations in male zebrafish behavior, particularly affecting fear responses, aggression, and anxiety-related behaviors. We believe that these findings could contribute to a deeper understanding of the relationship between androgens and behaviors in vertebrates, especially zebrafish. Full article

Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms. Over the past two decades, the treatment paradigm has evolved from monotherapy with androgen deprivation therapy (ADT) to a multifaceted approach integrating chemotherapy, androgen receptor axis-targeted therapies (ARATs), radiopharmaceuticals, and precision medicine. This review explores the molecular underpinnings of PCa, including genetic and epigenetic alterations such as BRCA1/2, TP53, and PTEN mutations, and their role in disease progression and treatment resistance. We detail the evidence supporting the integration of systemic agents like abiraterone, enzalutamide, and darolutamide into both hormone-sensitive and castration-resistant settings. Furthermore, we highlight the expanding role of radioligand therapies, including radium-223 and Lutetium-177-labeled PSMA-617 (Lu-PSMA-617), as well as the growing impact of PARP inhibitors in genomically selected patients. The emergence of theranostic strategies and next-generation sequencing has paved the way for personalized treatment algorithms, moving toward a truly precision oncology model in PCa. This comprehensive review synthesizes current therapeutic strategies, clinical trial evidence, and future directions aimed at optimizing outcomes and quality of life for patients with advanced prostate cancer. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry is facilitated by transmembrane protease serine 2 (TMPRSS2), which is regulated by the androgen receptor (AR). Androgen deprivation therapy (ADT), widely used in prostate cancer treatment, may potentially modulate TMPRSS2 expression, affecting SARS-CoV-2 infection susceptibility and severity. We evaluated the impact of ADT on pulmonary TMPRSS2 expression in prostate cancer patients and analyzed differences in expression patterns associated with specific ADT regimens. We examined TMPRSS2 immunohistochemical expression in lung tissue from 20 consecutive autopsy cases of men with prostate cancer (6 receiving ADT at time of death), compared with non-ADT prostate cancer patients and age-matched women controls. Histoscores were calculated by assessing the percentage and intensity of pneumocyte TMPRSS2 expression. Prostate cancer patients receiving ADT showed significantly reduced pulmonary TMPRSS2 expression compared to non-ADT patients (mean histoscores: 152.7 vs. 225.0, p = 0.037) and age-matched women controls (mean histoscores: 152.7 vs. 238.0, p = 0.024). Direct AR antagonists (apalutamide, bicalutamide) produced greater TMPRSS2 suppression than Gonadotropin-Releasing Hormone modulators or androgen biosynthesis inhibitors. No significant correlation was observed between the TMPRSS2 expression and Gleason score, PSA levels, or underlying lung pathology. Our findings demonstrate that ADT significantly reduces pulmonary TMPRSS2 expression, with direct AR antagonists showing the strongest effect. This suggests a potential mechanistic explanation for differential COVID-19 susceptibility and provides a rationale for investigating AR-targeted therapies as potential protective interventions against SARS-CoV-2 infection severity. Full article

Background and Objective: Prostate cancer (PC) is the most common cancer among males in the Western World. Androgens are key growth regulators both in normal and malignant prostate growth. Several new types of androgen pathway inhibitors (ARPIs) have been developed for the treatment of PC. Despite the lack of evidence, sequential use of ARPIs has been adopted into everyday clinical practice. This study aimed to assess real-life ARPI use patterns, especially sequential use and treatment costs, in Finland. Methods: Nationwide register data on all ARPI (enzalutamide, apalutamide, darolutamide, abiraterone) purchases recorded in the National Health Insurance scheme register maintained by the Social Insurance Institution of Finland from January 2012 to December 2023 were used. The data included patient demographics and medicine purchase details, which were descriptively analysed. Results: During the study period, 8369 patients initiated ARPIs. The median age of the users was 75.1 years. Of these, 32.1% (n = 2685) used at least two ARPIs sequentially. The proportion of treatment initiations leading to sequential use increased from 36% in 2012 to 56% in 2017, then decreased to 14% in 2022. The total cost of sequential use was €43.8 million. Limitations include the unrecorded phase of PC. The study’s strength is its inclusion of all reimbursed ARPI purchases nationwide. Conclusions: Despite the lack of evidence, sequential ARPI use was initially prevalent but declined after the introduction of new guidelines. Randomised trials are needed to guide the sequential use of these medicines. Patient summary: Androgen pathway inhibitors (ARPIs) are widely used in prostate cancer in Finland. One-third of patients use at least two ARPIs sequentially to inhibit testosterone effect. However, there are no large clinical trials published demonstrating the benefits of sequential treatment. More evidence is needed to justify sequential use. Full article

Background: Accurate assessment of CYP2C induction-mediated drug–drug interactions (DDIs) remains a challenge, despite the importance of CYP2C enzymes in drug metabolism. Limitations in available models and scarce clinical induction data have hampered quantitative preclinical DDI risk evaluation. Methods: In this study, the authors utilized an all-human hepatocyte triculture system to capture CYP2C induction using the perpetrators rifampicin, efavirenz, carbamazepine, and apalutamide. In vitro induction parameters were quantified by measuring changes in both mRNA and enzyme activities for CYP2C8, CYP2C9, and CYP2C19. These induction parameters, along with CYP-specific intrinsic clearance (CL_int) for the victim compounds, were incorporated into a physiologically based pharmacokinetic (PBPK) model, and pharmacokinetics (PK) of known CYP2C substrates were predicted with and without co-administration of perpetrator compounds using clinical dosing regimens. The results were quantitatively compared with the currently utilized mechanistic static modeling (MSM) approach and the reported clinical DDI outcomes. Results: By incorporating the measured f_m of CYP2C substrates into PBPK modeling, we observed a lower propensity to over- or underpredict the exposure of these substrates as victims of CYP2C induction-based DDIs when co-administered with known perpetrators, which resulted in an excellent correlation to observed clinical outcomes. The MSM approach predicted the CYP3A4 induction-based DDI risk accurately but could not capture CYP2C induction with similar precision. Conclusions: Overall, this is the first study that demonstrates the utility of PBPK modeling as a complementary approach to MSM for CYP2C induction-based DDI risk assessment. Full article

Background/Objectives: Androgen deprivation therapy (ADT) is the mainstay of prostate cancer treatment, especially in advanced disease. In particular, the gonadotropin-releasing hormone agonists (aGnRH) reduce the production of gonadotropin and, therefore, of testosterone. In about 10% of patients, the non-pulsatile stimulation of GnRH receptor initially causes a surge in LH and testosterone, defined as the “flare-up phenomenon”, leading to increased bone pain, spinal cord compression, bladder outlet obstruction and cardiovascular issues. To mitigate this effect, combining a first-generation antiandrogen agent (FGA) with aGnRH is recommended. However, second-generation anti-androgens, such as apalutamide, bind selectively and irreversibly to the androgen receptor (AR), exhibiting a more efficient inhibition of the AR pathway. Methods: This is a descriptive retrospective study of 27 patients (pts) with mHSPC, treated at a single center (“Santa Maria delle Grazie” Hospital in Pozzuoli, ASL Napoli 2 Nord, Italy) between June 2022 and April 2024. Patients received apalutamide monotherapy for 14 days followed by continuous combination with aGnRH plus apalutamide. Serum PSA and testosterone levels were measured at baseline, at day 14 (after 13 days of apalutamide monotherapy), at day 28 (after an additional 15 days of apalutamide plus a aGnRH), and at day 60. Results: PSA levels decreased from a mean of 45.2 (±63.1) ng/mL at baseline to a mean of 12.6 (±23.4) ng/mL at day 14 and to 3.3 ng/mL (±6.0) at day 28 of treatment. After 14 days of apalutamide monotherapy, 21 patients (77.8%) achieved a >50% PSA reduction and 4 (14.8%) a >90% PSA reduction. The number of patients with undetectable PSA was one (3.7%) at day 14, two (7.4%) at day 28, and nine (33.3%) at day 60. The mean serum testosterone levels were 6.56 (±4.46) ng/mL at baseline, 6.58 (±4.42) ng/mL at day 14, and 2.40 (± 3.38) ng/mL at day 28. No significant difference in PSA and testosterone level reduction during treatment emerged between subgroups of patients with low- vs. high-volume disease. Conclusions: Apalutamide alone is a viable option for mitigating the flare-up phenomenon, avoiding first generation anti-androgen therapy, and it can achieve rapid and deep biochemical control. Full article

Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the integration of androgen receptor signaling inhibitors (ARSIs) and metastasis-directed therapies (MDTs). Stereotactic body radiotherapy (SBRT) offers precise local control, yet real-world data on its combination with apalutamide remain limited. Methods: We conducted a multicenter retrospective cohort study including 134 patients with mHSPC treated with apalutamide and SBRT between February 2021 and December 2024. The primary endpoints were progression-free survival (PFS), local control (LC), and treatment safety. PSA kinetics and radiologic response were evaluated, and outcomes were analyzed according to PSA thresholds and treatment timing. Results: Most patients (93.3%) had low-volume disease; 97.1% presented with ≤5 metastases. At a median follow-up of 28 months, LC was 99.3% and 95.5% of patients were progression-free. Complete radiological response was achieved in 87.5% of patients, and 68.4% attained ultralow PSA levels (≤0.02 ng/mL). Undetectable PSA and radiologic complete response were independently associated with improved PFS (p = 0.010 and p = 0.011, respectively). Treatment was well tolerated, with grade ≥3 toxicity occurring in only 2.2% of patients. Conclusions: The combination of apalutamide and SBRT in mHSPC is associated with high local and systemic disease control and minimal toxicity in a real-world setting. This approach may delay systemic treatment intensification and the onset of castration resistance. Prospective studies are warranted to confirm these findings. Full article

The treatment of choice for prostate cancer is androgen deprivation (ADT) and novel hormonal agents such as Abiraterone, Enzalutamide, or Apalutamide. Initially, this therapy is highly effective, but a significant challenge arises as most patients eventually develop resistance, resulting in castration-resistant prostate cancer (CRPC). Furthermore, the sequential use of these drugs can lead to cross-resistance, diminishing their efficacy. Tumor heterogeneity plays a pivotal role in the development of resistance to different treatments. This study utilized cellular models of CRPC to assess the response to Apalutamide when it was administered as a second- or third-line treatment. Functional and genetic analyses were conducted in various CRPC cell models exposed to Apalutamide. These analyses included real-time cell monitoring assays, flow cytometry, clonogenicity assays, and RT-qPCR. CRPC cell models were capable of continued proliferation, maintained cell cycle profiles similar to those of untreated cells, and retained their clonogenic potential. Cross-resistance to Apalutamide in models of ADT, ADT plus Enzalutamide, or Abiraterone resistance did not correlate with the expression levels of AR-V7 and AR-V9 variants. Gene expression analysis of resistant prostate cancer cell lines revealed that treatment with Apalutamide induced the emergence of more aggressive phenotypes, including cancer stem cells or neuroendocrine differentiation profiles. Most CRPC cell models developed cross-resistance to Apalutamide and were able to proliferate and retain their clonogenic capability. Apalutamide resistance was not linked to the expression of AR-V7 or AR-V9 variants but was instead associated to bypass of AR signaling pathway and the emergence of more aggressive expression profiles. Full article

Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved significantly in recent years due to the introduction of androgen receptor-targeted agents (ARTAs). When used alongside androgen deprivation therapy (ADT), these treatments have shown improved oncological results and enhanced survival rates for patients with this condition. Objectives: The objective of this study was to describe the decline in prostate-specific antigen (PSA), the oncological outcomes, and the toxicity profile of mHSPC patients treated with apalutamide. Materials and Methods: Clinical data obtained from seven national hospitals were utilized between March 2021 and July 2024. PSA responses were collected at 3, 6, 12, 18, and 24 months, along with adverse effects reported by patients, dose reductions, or drug discontinuations. The association between PSA decline and progression-free survival (PFS) was evaluated with respect to metastasis volume, location, and timing of diagnosis. Results: A total of 432 patients were included, of whom 40% were de novo cases, and the greater part were classified as M1b. After one year, a reduction of more than 90% in PSA levels was observed in 88.2% of cases, with undetectable levels (≤0.2 ng/mL) achieved in 81.7% of them. The drug was discontinued in 76 patients (15.6%), with adverse effects reported in 7.8% (grade 3) and 1.9% (grade 4). Regarding PSA levels <0.02 ng/mL, promising results were observed, with ultralow PSA (UL2) achieved in 43% of cases at 6 months. Conclusions: This study revealed strong oncological outcomes, with rapid and profound PSA declines and drug safety consistent with emerging evidence. The distinctive finding of this study underscores the importance of a rapid and profound response (UL PSA) as a predictor of better oncological outcomes. Full article

Background: Gleason scores of 8 or higher indicate a poorer prognosis in metastatic castration-sensitive prostate cancer (mCSPC). This study aims to perform a systematic review and network meta-analysis (NMA) to compare overall survival (OS) and progression-free survival (PFS) among combination therapies with androgen receptor signaling inhibitors (ARSIs) in mCSPC patients, stratified by Gleason score ≥8 and <8. Methods: A literature search was conducted across PubMed, Embase, and Web of Science, using a PRISMA-guided systematic search strategy, covering January 2013 to June 2024. Results: Twelve studies including 12,652 patients were included in the NMAs. In the overall population, most ARSI combination therapies improved survival outcomes, except for orteronel + androgen deprivation therapy (ADT). In the Gleason score ≥8 subgroup, all ARSI combination therapies improved OS, with rezvilutamide showing the highest probability of being the best treatment for OS (HR 0.48, 95% CI 0.31–0.76, P-scores 0.88). In the Gleason score <8 subgroup, only darolutamide + docetaxel + ADT (HR 0.49, 95% CI 0.29–0.81) and apalutamide + ADT (HR 0.67, 95% CI 0.46–0.98) improved OS. Conclusions: ARSI combination therapy is effective for mCSPC patients with Gleason score ≥8, but further investigation is needed to confirm its efficacy in patients with Gleason score <8. Full article

Background/Objectives: Several drugs used to treat prostate cancer have been reported to cause cardiovascular adverse events, and this study sought to identify the real-world risk. Methods: This study utilized real-world data from the FAERS to analyze the association between prostate cancer treatment and cardiovascular adverse events. It evaluated men treated with LHRH agonists and antagonists, antiandrogens, androgen synthesis inhibitors, and PARP inhibitors from 2003 to 2023. This study included patients treated with leuprolide, goserelin, triptorelin, degarelix, relugolix, bicalutamide, flutamide, apalutamide, nilutamide, abiraterone, enzalutamide, olaparib, rucaparib, talazoparib, and niraparib. The main outcome measure was the reported odds ratio (ROR) of adverse cardiovascular event associated with these treatments. Results: Among the 4,049,329 unique adverse event reports, 4391 cardiovascular events were identified. Leuprolide (ROR 0.481, 95% CI: 0.423–0.547), triptorelin (ROR 0.527, 95% CI: 0.305–0.909), enzalutamide (ROR 0.393, 95% CI: 0.341–0.452), and olaparib (ROR 0.145, 95% CI: 0.054–0.386) reduced the risk of myocardial infarction. Goserelin increased the risk of myocardial infarction (ROR 2.235, 95% CI: 1.367–3.654). Degarelix and relugolix both increased the risk of heart failure (ROR 3.136, 95% CI: 2.186–4.497), and enzalutamide was associated with an increased risk of heart failure (ROR 1.305, 95% CI: 1.135–1.501). Bicalutamide increased the risk of unstable angina (ROR 3.019, 95% CI: 1.621–5.622) and heart failure (ROR 3.730, 95% CI: 3.085–4.510). Niraparib increased the risk of hypertension (ROR 4.154, 95% CI: 1.709–10.092). Conclusions: These findings underscore the need for clinicians to monitor cardiac complications in patients undergoing these therapies. Full article

Background/Objectives: Androgen receptor-targeted agents have significantly improved the prognosis of metastatic hormone-sensitive prostate cancer (mHSPC). Prostate-specific antigen (PSA) levels are key prognostic markers, with rapid and deep reductions associated with better outcomes. This study aims to assess the association between the new PSA cut-offs and survival in mHSPC patients treated with Apalutamide. Methods: We conducted a multicentre, retrospective analysis of mHSPC patients treated with Apalutamide between March 2021 and January 2023. Overall survival (OS) and radiographic progression-free survival (rFPS) were analyzed and stratified by the following PSA ranges: <0.02 ng/mL (ultralow), 0.02–0.2 ng/mL, and >0.2 ng/mL. Cox regression was applied to identify variables associated with OS and rPFS. Results: Among 193 patients, 34.2% had de novo mHSPC, with the majority classified as M1b. A total of 58.2% (110) of our cohort achieved ultralow PSA levels, with 20.6% between 0.02 and 0.2 ng/mL, and 21.2% of PSA levels > 0.2 ng/mL. Most patients reached ultralow PSA within six months. Low-volume, metachronous, and M1a subgroups displayed a higher prevalence of patients reaching ultralow PSA levels. At 18 months, OS was 100% in the ultralow PSA group, 94.4% for the 0.02–0.2 ng/mL group, and 67.7% in the >0.2 ng/mL group. Similarly, rPFS at 18 months was 100%, 93.5%, and 50.7%, respectively. Cox regression revealed that both ultralow PSA levels and ISUP grade had a significant impact on OS (HR of 8.256 and 0.164, respectively). For rPFS, only ultralow PSA levels had a significant impact (HR = 0.085). Conclusions: This real-world study of mHSPC patients treated with Apalutamide plus ADT revealed that achieving ultralow PSA levels is strongly associated with better oncological outcomes. Full article

Background/Objectives: Abiraterone acetate, apalutamide, darolutamide, and enzalutamide, which make up the androgen receptor axis-targeted therapies (ARATs) drug class, are commonly used in the management of prostate cancer. Many patients on ARATs also receive oral antithrombotic therapy (i.e., anticoagulants or antiplatelets). The concomitant use of ARATs and antithrombotic therapies creates the potential for clinically relevant drug–drug interactions, but the literature regarding the actual consequences of these interactions, and guidance for co-prescribing, is limited. We assembled a multidisciplinary panel of experts and provided them with clinical information derived from a comprehensive literature review regarding the drug–drug interactions between ARATs and antithrombotic therapies. Methods: A three-stage modified electronic Delphi process was used to gather and consolidate opinions from the panel. Each stage consisted of up to three rounds of voting to achieve consensus on which ARAT/antithrombotic therapy drug pairs warrant attention, the possible clinical consequences of drug–drug interactions, and suggested actions for management. Results: The panel achieved consensus to avoid 11 ARAT/antithrombotic therapy drug pairs and modify therapy for eight pairs. Assessments relied heavily on pharmacokinetic data and extrapolation from drug–drug interaction studies of similarly metabolized drugs. Conclusions: This e-Delphi process highlights the need for further research into the clinical impact of ARAT/antithrombotic drug interactions. Nonetheless, the suggested actions aim to provide clinicians with a practical framework for therapeutic decision making. Full article

We conducted a retrospective evaluation of the clinical outcomes and prognostic factors in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with first-line androgen receptor signaling inhibitors (ARSI) in real-world clinical practice in Japan. Between 2012 and 2023, a total of 127 consecutive patients with nmCRPC received ARSI treatment. Overall survival (OS), metastatic-free survival (MFS), and prostate-specific antigen–progression-free survival (PSA–PFS) from ARSI initiation were assessed using the Kaplan–Meier methodology. Clinical factors associated with OS in nmCRPC were analyzed using the Cox proportional hazards model. Among the patients, 72, 26, 12, and 17 received enzalutamide (ENZ), abiraterone (ABI), apalutamide (APA), and darolutamide (DARO) as first-line therapy. The median OS and MFS for all patients were 79.0 and 42.0 months, respectively. Median PSA–PFS was 27.0, 20.0, 10.0, and 14.0 months for patients treated with ENZ, ABI, APA, and DARO, respectively (p = 0.33). Multivariate analysis revealed that a baseline PSA level ≥ 3.67 ng/mL at ARSI initiation was significantly associated with poorer OS (p = 0.002). ARSI demonstrated favorable efficacy in nmCRPC patients. There were no significant differences in clinical outcomes among different types of ARSI therapy for nmCRP. Elevated baseline PSA at ARSI initiation was significantly associated with poorer OS. Full article