Asunto(s)
Antagonistas de Andrógenos , Prostatectomía , Neoplasias de la Próstata , Tiohidantoínas , Humanos , Prostatectomía/métodos , Masculino , Tiohidantoínas/administración & dosificación , Tiohidantoínas/uso terapéutico , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Non-metastatic castration-resistant prostate cancer (nmCRPC) is an asymptomatic condition with the potential to progress to metastasis. Novel hormonal agents (NHAs) are currently considered the gold standard treatment for nmCRPC, offering significant survival benefits. However, further evidence is needed to determine whether there are differences in the performance of these drugs among Asian populations. METHODS: This retrospective analysis of nmCRPC patients aims to compare the efficacy and safety of three NHAs-apalutamide, darolutamide, and enzalutamide. Data were collected from two prominent prostate care centers in Taichung, Taiwan. Patient characteristics, treatment details, PSA responses, and adverse events were analyzed. Statistical comparisons were performed, and the study received Institutional Review Board approval. RESULTS: Total of 64 patients were recruited in this study, including 29 darolutamide, 26 apalutamide, and 9 enzalutamide patients. Baseline characteristics varied between the three patient groups, but the treatment response still revealed similar results. The apalutamide group experienced more adverse events, notably skin rash. Discontinuation rates due to adverse events differed among the groups, and patients receiving darolutamide were less likely to discontinue treatment. CONCLUSION: This real-world study provides insights into NHA utilization in nmCRPC within the Taiwanese population. Adverse event profiles varied, emphasizing the need for individualized treatment decisions. The study underscores the importance of regional considerations and contributes valuable data for optimizing treatment outcomes in nmCRPC.
Asunto(s)
Benzamidas , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Tiohidantoínas , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Feniltiohidantoína/uso terapéutico , Taiwán , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Estudios Retrospectivos , Persona de Mediana Edad , Tiohidantoínas/uso terapéutico , Tiohidantoínas/efectos adversos , Anciano de 80 o más Años , Pirazoles/uso terapéutico , Pirazoles/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Resultado del Tratamiento , Antígeno Prostático Específico/sangreRESUMEN
Metabolic reprogramming and mitochondrial dynamics are pivotal in prostate cancer (PCa) progression and treatment resistance, making them essential targets for therapeutic intervention. In this study, we investigated the effects of the androgen receptor antagonist apalutamide (ARN) and the mitochondrial electron transport chain complex I inhibitor IACS-010759 (IACS) on the mitochondrial network architecture and dynamics in PCa cells. Treatment with ARN and/or IACS induced significant changes in mitochondrial morphology, particularly elongation, in androgen-sensitive PCa cells. Additionally, ARN and IACS modulated the mitochondrial fission and fusion processes, indicating a convergence of metabolic and androgen-signaling pathways in shaping mitochondrial function. Notably, the combination treatment with ARN and IACS resulted in increased apoptotic cell death and mitochondrial oxidative stress selectively in the androgen-sensitive PCa cells. Our findings highlight the therapeutic potential of targeting mitochondrial metabolism in prostate cancer and emphasize the need for further mechanistic understanding to optimize treatment strategies and improve patient outcomes.
Asunto(s)
Apoptosis , Complejo I de Transporte de Electrón , Mitocondrias , Neoplasias de la Próstata , Especies Reactivas de Oxígeno , Tiohidantoínas , Humanos , Masculino , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Tiohidantoínas/farmacología , Tiohidantoínas/uso terapéutico , Línea Celular Tumoral , Complejo I de Transporte de Electrón/metabolismo , Complejo I de Transporte de Electrón/antagonistas & inhibidores , Dinámicas Mitocondriales/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéuticoRESUMEN
Apalutamide, a novel endocrine therapy agent, has been shown to significantly improve the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, resistance to apalutamide has also been reported, and the underlying mechanism for this response has yet to be clearly elucidated. First, this study established apalutamide-resistant prostate cancer (PCa) cells, and confirmed that apalutamide activated the release of calcium ions (Ca2+) and endoplasmic reticulum stress (ERS) to enhance autophagy. Second, RNA sequencing, western blotting, and immunohistochemistry revealed significantly decreased Calpain 2 (CAPN2) expression in the apalutamide-resistant PCa cells and tissues. Furthermore, immunofluorescence and transmission electron microscopy (TEM) showed that CAPN2 promoted apalutamide resistance by activating protective autophagy. CAPN2 promoted autophagy by reducing Forkhead Box O1 (FOXO1) degradation while increasing nuclear translocation via nucleoplasmic protein isolation and immunofluorescence. In addition, FOXO1 promoted protective autophagy through the transcriptional regulation of autophagy-related gene 5 (ATG5). Furthermore, a dual-fluorescence assay confirmed that transcription factor 3 (ATF3) stimulation promoted CAPN2-mediated autophagy activation via transcriptional regulation. In summary, CAPN2 activated protective autophagy by inhibiting FOXO1 degradation and promoting its nuclear translocation via transcriptional ATG5 regulation. ATF3 activation and transcriptional CAPN2 regulation jointly promoted this bioeffect. Thus, our findings have not only revealed the mechanism underlying apalutamide resistance, but also provided a promising new target for the treatment of metastatic PCa.
Asunto(s)
Autofagia , Calpaína , Resistencia a Antineoplásicos , Metástasis de la Neoplasia , Neoplasias de la Próstata , Tiohidantoínas , Humanos , Masculino , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Calpaína/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Tiohidantoínas/farmacología , Tiohidantoínas/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteína Forkhead Box O1/metabolismo , Calcio/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , AnimalesRESUMEN
PURPOSE: To assess the efficacy and safety of apalutamide plus goserelin for androgen receptor (AR)-positive unresectable or recurrent/metastatic salivary gland carcinoma. PATIENTS AND METHODS: This trial was an open-label, single-arm, multicenter phase II study. Patients with histologically confirmed unresectable or recurrent/metastatic salivary gland carcinoma with AR expression were included. The primary endpoint was the overall response rate (ORR) according to RECIST v1.1 by an independent central radiology review in the first 24 response-evaluable (RE) patients who had been observed at least 24 weeks from study initiation (primary RE patients). The efficacy was to be declared when at least 8 of the 24 primary RE patients responded. RESULTS: A total of 31 patients were enrolled. In the first 24 primary RE patients with a median follow-up of 7.4 months, confirmed ORR by independent central radiology review was 25.0% [6/24 patients; 95% confidence interval, 9.8%-46.7%; P = 0.11 (one-sided)], which did not meet the predefined criteria of efficacy. Clinical benefit rate (ORR + rate of stable disease for at least 24 weeks) and median progression-free survival were 50.0% and 7.4 months, respectively. Both median duration of response and overall survival were not reached. Exploratory analyses showed a better ORR of 54.5% (6/11) in patients with AR positivity ≥70% and no history of prior systemic therapy. Grade 3 or higher treatment-emergent adverse events were reported in 35.5% (11/31), which included skin rash, anemia, leukopenia, and cancer pain. CONCLUSIONS: Although this study did not meet the predefined efficacy criteria, apalutamide plus goserelin showed clinically meaningful efficacy in a subset of patients with AR-positive salivary gland carcinoma and safety consistent with prior experience in prostate cancer.
Asunto(s)
Goserelina , Receptores Androgénicos , Neoplasias de las Glándulas Salivales , Tiohidantoínas , Humanos , Masculino , Persona de Mediana Edad , Femenino , Anciano , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/mortalidad , Receptores Androgénicos/metabolismo , Tiohidantoínas/administración & dosificación , Tiohidantoínas/uso terapéutico , Tiohidantoínas/efectos adversos , Adulto , Goserelina/administración & dosificación , Goserelina/uso terapéutico , Goserelina/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Resultado del Tratamiento , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patologíaRESUMEN
OBJECTIVE: To analyse the adverse events (AEs) associated with apalutamide and the impact of a multidisciplinary team (MDT) protocol on its management at a tertiary care hospital in a real-world setting. METHODS: This was an observational, prospective, cohort study based on real-world evidence at the Hospital Clínic de Barcelona. Includes patients diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) or high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC) and who started treatment with apalutamide between May 2019 and March 2023 in a real-world clinical setting. RESULTS: Of the 121 patients treated with apalutamide, 52.1% experienced an AE, 19.8% experienced temporarily interruption or a reduction in the dose of apalutamide, and 13.2% discontinued treatment due to AEs. Without MDT protocol (49 patients), 24.5% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 10.1 months, and 24.5% discontinued apalutamide due to AEs, with a median time from the start of treatment of 3.1 months. Meanwhile, whit MDT protocol (72 patients), 16.7% of patients had to temporarily interrupt or reduce the dose of apalutamide due to AEs, with a median time from the start of treatment of 1.6 months, and 5.6% discontinued apalutamide due to AEs, with a median time from the start of treatment of 4 months. The risk reduction associated with treatment discontinuation was statistically significant (p-value = 0.003). CONCLUSIONS: This study highlights the importance of MDT management of AEs associated with apalutamide to reduce treatment discontinuation.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Tiohidantoínas , Humanos , Masculino , Tiohidantoínas/efectos adversos , Tiohidantoínas/uso terapéutico , Tiohidantoínas/administración & dosificación , Anciano , Estudios Prospectivos , Neoplasias de la Próstata/tratamiento farmacológico , Persona de Mediana Edad , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Grupo de Atención al Paciente , Anciano de 80 o más Años , Estudios de Cohortes , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificaciónRESUMEN
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.
Asunto(s)
Antagonistas de Andrógenos , Neoplasias de la Próstata , Tiohidantoínas , Anciano , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Andrógenos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Fase II como Asunto , Metástasis de la Neoplasia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Antígeno Prostático Específico/sangre , Prostatectomía/métodos , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/terapia , Tiohidantoínas/uso terapéutico , Tiohidantoínas/administración & dosificaciónAsunto(s)
Enfermedades Pulmonares Intersticiales , Tiohidantoínas , Humanos , Masculino , Enfermedades Pulmonares Intersticiales/inducido químicamente , Tiohidantoínas/uso terapéutico , Anciano , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patologíaRESUMEN
OBJECTIVE: Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10 months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. METHODS: This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. RESULTS: No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10 months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. CONCLUSION: In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.
Asunto(s)
Benzamidas , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Tiohidantoínas , Humanos , Masculino , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Estudios Retrospectivos , Tiohidantoínas/uso terapéutico , Tiohidantoínas/efectos adversos , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Antígeno Prostático Específico/sangre , Resultado del TratamientoRESUMEN
INTRODUCTION: Second-generation androgen receptor axis-targeting (ARAT) agents have become a standard treatment for patients with advanced prostate cancer (PC), however much remains unknown about the potential cardiovascular toxicities. PATIENTS AND METHODS: We performed a systematic search of PubMed, Embase, Web of Science, and Cochrane library for randomized controlled trials of patients receiving ARAT agents for PC from inception to March 2023. The odds ratios (ORs) of all-grade and high-grade cardiovascular adverse events (CVAEs) for patients treated with and without ARAT agents were pooled for meta-analysis. Subgroup analyses based on PC type and treatment regimen were conducted. RESULTS: A total of 15 double-blind placebo-controlled phase 3 trials comprising 15,842 patients were included. In addition to hot flush and hypertension of any degree of severity, inclusion of ARAT agents was associated with a significantly higher risk of acute myocardial infarction (OR: 1.96, 95% CI: 1.05-3.68, P = .04), myocardial infarction (OR: 2.44, 95% CI: 1.27-4.66, P = .007) and angina pectoris (OR: 2.00, 95% CI: 1.00-4.02, P = .05). With regard to individual ARAT agents, enzalutamide was associated with a significantly higher risk of acute myocardial infarction (OR: 3.11, 95% CI: 1.17-8.28, P = .02), coronary artery disease (OR: 8.33, 95% CI: 1.54-44.95, P = .01), and high-grade hypertension (OR: 4.94, 95% CI: 1.11-22.06, P = .04), while abiraterone and apalutamide were associated with a significantly higher risk of angina pectoris (OR: 5.48, 95% CI: 1.23-24.33, P = .03) and myocardial infarction (OR: 7.00, 95% CI: 1.60-30.62, P = .01), respectively. CONCLUSION: The inclusion of ARAT agents was associated with a significantly higher risk of several CVAEs. Clinicians should remain vigilant, both in pre-treatment screening and monitoring for clinical symptoms and signs, when considering ARAT agent particularly for patients with pre-existing risk factors.
Asunto(s)
Neoplasias de la Próstata , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Enfermedades Cardiovasculares/inducido químicamente , Antagonistas de Receptores Androgénicos/efectos adversos , Antagonistas de Receptores Androgénicos/uso terapéutico , Antagonistas de Receptores Androgénicos/administración & dosificación , Receptores Androgénicos/metabolismo , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/administración & dosificación , Benzamidas/efectos adversos , Ensayos Clínicos Fase III como Asunto , Nitrilos/efectos adversos , Tiohidantoínas/efectos adversos , Tiohidantoínas/administración & dosificación , Tiohidantoínas/uso terapéutico , Androstenos/efectos adversos , Androstenos/uso terapéutico , Androstenos/administración & dosificaciónRESUMEN
PURPOSE: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers. PATIENTS AND METHODS: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies. RESULTS: Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and 3 (n = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The aggressive-variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with unsatisfactory status. Exploratory analyses suggested that secreted phosphoprotein 1-positive and insulin-like growth factor-binding protein 2-positive macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the unsatisfactory group. CONCLUSIONS: Adding ipilimumab to AAPA did not improve outcomes in men with androgen-responsive metastatic castration-resistant prostate cancer. Despite the addition of carboplatin + cabazitaxel, men in the unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.
Asunto(s)
Acetato de Abiraterona , Protocolos de Quimioterapia Combinada Antineoplásica , Prednisona , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/uso terapéutico , Acetato de Abiraterona/uso terapéutico , Acetato de Abiraterona/administración & dosificación , Tiohidantoínas/administración & dosificación , Tiohidantoínas/uso terapéutico , Tiohidantoínas/efectos adversos , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/uso terapéutico , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , TaxoidesRESUMEN
Studies of patients with castrate-resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non-metastatic castrate-resistant prostrate cancer have demonstrated increased metastasis-free survival and overall survival following treatment with the next-generation oral anti-androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone-releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be managed proactively to minimize their impact on patients. Monitoring of patients for apalutamide-specific toxicities, including skin rash, hypothyroidism, and QT prolongation should be carried out regularly, particularly in the first few months following initiation. Monitoring should continue alongside monitoring for toxicities of androgen deprivation, including cardiovascular risk, hot flashes, weight gain, bone health, muscle wasting, and diabetic risk. This review is a practical guide to the use of apalutamide describing the management of patients including dosing and administration, toxicities, potential drug interactions, and safety monitoring requirements.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Tiohidantoínas , Humanos , Masculino , Tiohidantoínas/administración & dosificación , Tiohidantoínas/uso terapéutico , Tiohidantoínas/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Australia , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Guías de Práctica Clínica como AsuntoRESUMEN
This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e ., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Docetaxel , Metaanálisis en Red , Humanos , Masculino , Antagonistas de Andrógenos/uso terapéutico , Androstenos/uso terapéutico , Androstenos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Docetaxel/uso terapéutico , Docetaxel/administración & dosificación , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Pirazoles , Ensayos Clínicos Controlados Aleatorios como Asunto , Tiohidantoínas/uso terapéutico , Tiohidantoínas/administración & dosificaciónRESUMEN
Nearly all men with metastatic hormone-sensitive prostate cancer treated with intermittent androgen deprivation therapy (ADT) experience recurrence within 6 mo of testosterone recovery. We conducted a single-arm phase 2 trial to evaluate whether addition of dual androgen receptor pathway inhibitors (ARPIs) and metastasis-directed stereotactic body radiotherapy (SBRT) to intermittent ADT improves recurrence rates for men with between one and five nonvisceral, extrapelvic metastases on prostate-specific membrane antigen positron emission tomography/computed tomography after prior radical prostatectomy. Patients received 6 mo of androgen annihilation therapy (AAT; leuprolide, abiraterone acetate plus prednisone, and apalutamide) and metastasis-directed SBRT. The primary endpoint was the percentage of patients with prostate-specific antigen (PSA) <0.05 ng/ml 6 mo after testosterone recovery (≥150 ng/dl), with the study powered to detect an improvement from 1% to 12%. We enrolled 28 men between March 2021 and June 2022. Median follow-up was 20 mo (interquartile range 16-22). Twenty-six patients (93%) completed SBRT with 6 mo of hormone therapy, of whom six discontinued at least one ARPI; two patients withdrew prematurely. At 6 mo after testosterone recovery, PSA was maintained at <0.05 ng/ml in 13/26 patients (50%, 95% confidence interval 32-67%). Rates of grade 2 and 3 AAT toxicity were 21% and 21%. The results confirm that addition of metastasis-directed SBRT to highly potent systemic therapy can maintain low PSA after testosterone recovery, although further studies are needed to clarify the optimal systemic therapy regimen. PATIENT SUMMARY: We tested a combination of intensified hormone therapy (called androgen annihilation therapy) and radiotherapy targeted at metastases in men with recurrence of metastatic prostate cancer. We found that half of patients were recurrence-free 6 months after their testosterone level recovered, and that less than a quarter of patients experienced a severe drug-related side effect. Overall, this appears to be an effective therapy with acceptable side effects. This trial is registered on ClinicalTrials.gov as NCT03902951.
Asunto(s)
Leuprolida , Recurrencia Local de Neoplasia , Neoplasias de la Próstata , Radiocirugia , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Anciano , Leuprolida/uso terapéutico , Persona de Mediana Edad , Acetato de Abiraterona/uso terapéutico , Tiohidantoínas/uso terapéutico , Prednisona/uso terapéutico , Prednisona/administración & dosificación , Antígeno Prostático Específico/sangre , Metástasis de la Neoplasia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , Antagonistas de Andrógenos/uso terapéutico , Resultado del Tratamiento , Antineoplásicos Hormonales/uso terapéuticoAsunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Próstata/patología , Neoplasias de la Próstata/patología , Tiohidantoínas/uso terapéutico , Hormonas , Neoplasias de la Próstata Resistentes a la Castración/patología , Antagonistas de Andrógenos/uso terapéuticoRESUMEN
INTRODUCTION: This is a multicentre, open-label, single-arm clinical trial to evaluate the efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer. METHODS AND ANALYSIS: The trial will be performed at 4 university hospitals and 14 city hospitals in Japan. The target number of patients will be 110. The patients will be orally administered 240 mg apalutamide once daily during the treatment period. The primary outcome is the prostate-specific antigen (PSA) response rate. PSA response is defined as ≥50% decline from baseline at 12 weeks. Secondary outcomes are time to PSA progression, progression-free survival, overall survival, progression-free survival during second therapy, ≥50% decline in PSA from baseline at 24 and 48 weeks, ≥90% decline in PSA from baseline or lower PSA detection sensitivity after the initial dose at 12, 24 and 48 weeks, PSA maximal changes, accumulated PSA response from screening to 24 and 48 weeks, and grade 3 or 4 adverse events according to the Common Terminology Criteria for Adverse Events version 4.0. ETHICS AND DISSEMINATION: This study has been approved by the Certified Research Review Board of Kobe University (No. CRB5180009). All participants will be required to provide written informed consent. Findings will be disseminated through scientific and professional conferences and peer-reviewed journal publications. The datasets generated during the study will be available from the corresponding author on reasonable request. TRIAL REGISTRATION NUMBER: jRCTs051220077.
Asunto(s)
Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Tiohidantoínas/uso terapéutico , Supervivencia sin Progresión , Resultado del Tratamiento , Estudios Multicéntricos como AsuntoRESUMEN
The treatment of castration-sensitive prostate cancer (CSPC) has been revolutionized by the advent of apalutamide and enzalutamide in this setting; however, a direct comparison between these agents is still missing. In the current paper, we performed both Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses aimed to compare clinical outcomes in CSPC patients treated with apalutamide or enzalutamide; data from 3323 CSPC patients enrolled in the ARCHES, ENZAMET and TITAN phase III studies were included. According to our results, apalutamide showed better results in terms of overall survival (OS) and safety in patients with CSPC, while better outcomes were observed with enzalutamide in the low-volume subgroup.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Tiohidantoínas/uso terapéutico , CastraciónRESUMEN
BACKGROUND: Second-generation androgen receptor inhibitors (ARIs) have been associated with adverse events (AEs) such as fatigue, falls, fractures, and rash in non-metastatic castration-resistant prostate cancer (nmCRPC) patients as identified in clinical trials. The objectives of this study were to describe the incidence and management of AEs in patients receiving apalutamide and enzalutamide. METHODS: This retrospective chart review study was conducted in nmCRPC-treating sites in the United States. Patients starting apalutamide or enzalutamide between February 1, 2018 and December 31, 2018 were included and any AEs they experienced were recorded. AEs, including those considered to be of special interest as defined in the pivotal clinical trials of the second-generation ARIs, were analyzed and grouped retrospectively in this study. Detailed chart data (patient demographics, clinical characteristics, treatment history, type of AE, outcomes, and resource utilization) were then collected for a randomly selected subset among patients with ≥1 AE to characterize AEs and their management. Descriptive results were summarized. RESULTS: Forty-three sites participated in the study. A total of 699 patients were included, of whom 525 (75.1%) experienced ≥1 AE. The most common AEs were fatigue/asthenia (34.3%), hot flush (13.9%), and arthralgia (13.6%). In the subset of 250 patients randomly selected from those who experienced ≥1 AE, patients were primarily White (72.0%), the mean age was 71 years, 86.0% had an Eastern Cooperative Oncology Group score of 0-1 at nmCRPC diagnosis, and the average prostate specific antigen (PSA) value at diagnosis was 23.2 ng/mL. PSA-doubling time < 10 months was chosen as reason to initiate treatment in 40% of patients. The median duration of follow-up was 1.1 years, with 14.4% of patients progressing to metastasis by end of study period. Grade 3-4 and Grade 5 AEs occurred in 14.4 and 0.4% of patients, respectively. Actions taken to manage AEs included AE-directed treatment (38.0%), ARI discontinuation (10.4%), dose reduction (7.6%), and AE-related hospitalization (4.8%). CONCLUSIONS: This study highlights the burden of AEs among nmCRPC patients treated with apalutamide or enzalutamide, providing a relevant real-world benchmark as clinical trial evidence and the treatment landcape for nmCRPC continues to evolve.
Asunto(s)
Antagonistas de Receptores Androgénicos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Benzamidas/efectos adversos , Nitrilos/efectos adversos , Feniltiohidantoína/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Tiohidantoínas/efectos adversos , Anciano , Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Artralgia/inducido químicamente , Astenia/inducido químicamente , Benzamidas/uso terapéutico , Fatiga/inducido químicamente , Rubor/inducido químicamente , Hospitalización , Humanos , Masculino , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Estudios Retrospectivos , Tiohidantoínas/uso terapéutico , Estados UnidosRESUMEN
Several novel androgen receptor (AR)-inhibitors have been introduced for nonmetastatic castration-resistant prostate cancer (nmCRPC) treatment, with the improvement of survival outcomes which need to be balanced against the risk of adverse events. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) investigating enzalutamide, apalutamide and darolutamide in nmCRPC patients, to assess overall survival (OS), incidence and risk of adverse drug events, adverse-events-related death and adverse-events-related treatment discontinuation. We selected three RCTs (SPARTAN, PROSPER and ARAMIS). New hormonal agents administration resulted in better OS, despite the increased risk of several any grade and grade 3-4 adverse events. In the decision-making process, careful evaluation of expected adverse events, patients' comorbidities and maintenance of quality of life are mandatory.