ABSTRACT
BACKGROUND: Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =>12 years of age. This report provides details of patients who developed laboratory signs of hypothalamic-pituitary-adrenal (HPA) axis suppression without clinical signs of adrenal suppression during the clascoterone development program. METHODS: Two open-label, multicenter, Phase 2 trials evaluated HPA axis suppression in patients with moderate-to-severe acne vulgaris. Study 1 (NCT01831960) enrolled cohorts of adults =>18 years of age and adolescents =>12 to <18 years of age. Study 2 (NCT02720627) enrolled adolescents 9 to <12 years of age. Patients applied clascoterone twice daily at maximum-exposure dosages for 14 days. Adrenal suppression was evaluated via cosyntropin stimulation test (CST) at baseline and day 14. Patients with an abnormal CST result (serum cortisol level =<18 µg/dL) had a follow-up CST approximately 4 weeks later. Blood was collected for pharmacokinetic analysis. Other safety assessments included adverse events (AEs), physical examination/vital signs, and electrocardiography. RESULTS: Overall, 5/69 clascoterone-treated patients had an abnormal CST result on day 14, including 1/20 adults, 2/22 patients aged =>12 to <18 years, and 2/27 patients aged 9 to <12 years. All patients had normal cortisol levels at follow-up testing approximately 4 weeks later. No relationship was observed between abnormal CST results and clascoterone plasma concentrations or the amount of study drug applied. No clinically relevant AEs or clinically significant changes in safety measures were observed in patients with adrenal suppression. CONCLUSION: Clascoterone induced laboratory evidence of mild, reversible HPA axis suppression under maximum-use exposure. J Drugs Dermatol. 2024;23(6):433-437. doi:10.36849/JDD.7997.
Subject(s)
Acne Vulgaris , Hydrocortisone , Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Humans , Hypothalamo-Hypophyseal System/drug effects , Pituitary-Adrenal System/drug effects , Acne Vulgaris/drug therapy , Adolescent , Male , Female , Adult , Child , Young Adult , Hydrocortisone/blood , Cortodoxone/administration & dosage , Cortodoxone/analogs & derivatives , Cortodoxone/blood , Administration, Cutaneous , Skin Cream/administration & dosage , Skin Cream/adverse effects , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Treatment Outcome , Cosyntropin/administration & dosage , PropionatesABSTRACT
Recently, effectiveness of local treatment for oncological outcomes for patients with metastatic prostate cancer (PC) has been reported. We performed hemi-ablation with high-intensity focused ultrasound (HIFU) for a patient with a localized reducted solitary lesion in the prostate, which was diagnosed with magnetic resonance imaging (MRI)-transrectal ultrasound fusion image-guided target biopsy with PSA level of 0.24 ng/mL, after androgen receptor signaling inhibitors (ARSIs) and chemotherapy for metastatic PC. Prostate specific antigen levels decreased to 0.01ng/mL at 1 month after the treatment, and cancer suspicious lesion disappeared on MRI. During the follow-up of 24 months, there was no elevation of PSA level with no severe complication related to the treatment. HIFU has possibility to be an effective and minimally invasive treatment as a local treatment for the localized reducted solitary lesion in the prostate after ARSIs and chemotherapy for metastatic PC.
Subject(s)
Magnetic Resonance Imaging , Prostate-Specific Antigen , Prostatic Neoplasms , Humans , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms/therapy , Prostatic Neoplasms/diagnostic imaging , Treatment Outcome , Prostate-Specific Antigen/blood , Aged , High-Intensity Focused Ultrasound Ablation/methods , Image-Guided Biopsy/methods , Androgen Receptor Antagonists/administration & dosage , Prostate/pathology , Prostate/diagnostic imagingABSTRACT
INTRODUCTION: The therapeutic scenario of metastatic hormone-sensitive prostate cancer (mHSPC) has dramatically changed in recent years, with the approval of new-generation Androgen Receptor Signaling Inhibitors (ARSIs), in combination with the androgen deprivation therapy (ADT), which was the previous standard of care. Despite showing a similar clinical efficacy, ARSIs, all of which are administered orally, are different in terms of pharmacokinetic and drug-drug interactions (DDIs). AREAS COVERED: This review covers the main pharmacokinetic characteristics of ARSIs that have been approved for the first-line therapy of mHSPC patients, underlying the differences among these molecules and focusing on the known or possible interactions with other drugs. Full-text articles and abstracts were searched in PubMed. EXPERT OPINION: Since prostate cancer occurs mainly in older age, comorbidities and the consequent polypharmacy increase the DDI risk in mHSPC patients who are candidates for ARSI. Waiting for new therapeutic options, in the absence of direct comparisons, pharmacokinetic knowledge is essential to guide clinicians in prescribing ARSI in this setting.
Subject(s)
Androgen Receptor Antagonists , Drug Interactions , Neoplasm Metastasis , Prostatic Neoplasms , Signal Transduction , Humans , Male , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Androgen Receptor Antagonists/pharmacokinetics , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/pharmacology , Signal Transduction/drug effects , Polypharmacy , Aged , Androgen Antagonists/administration & dosage , Androgen Antagonists/pharmacokinetics , Androgen Antagonists/pharmacology , Androgen Antagonists/adverse effects , Administration, Oral , Antineoplastic Agents, Hormonal/pharmacokinetics , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Agents, Hormonal/pharmacology , AnimalsABSTRACT
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.
Subject(s)
Prostatic Neoplasms , Randomized Controlled Trials as Topic , Humans , Male , Prostatic Neoplasms/drug therapy , Cardiovascular Diseases/chemically induced , Androgen Receptor Antagonists/adverse effects , Androgen Receptor Antagonists/therapeutic use , Androgen Receptor Antagonists/administration & dosage , Receptors, Androgen/metabolism , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/therapeutic use , Phenylthiohydantoin/administration & dosage , Benzamides/adverse effects , Clinical Trials, Phase III as Topic , Nitriles/adverse effects , Thiohydantoins/adverse effects , Thiohydantoins/administration & dosage , Thiohydantoins/therapeutic use , Androstenes/adverse effects , Androstenes/therapeutic use , Androstenes/administration & dosageABSTRACT
PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Benzamides , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Receptors, Glucocorticoid , Humans , Male , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/therapeutic use , Phenylthiohydantoin/pharmacokinetics , Benzamides/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Nitriles/administration & dosage , Aged , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Aged, 80 and over , Neoplasm Metastasis , Androgen Receptor Antagonists/therapeutic use , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/pharmacokinetics , Androgen Receptor Antagonists/adverse effects , Receptors, Androgen/metabolism , Treatment OutcomeABSTRACT
BACKGROUND: Nonmetastatic castration-resistant prostate cancer (nmCRPC) patients are often older and use concurrent medications that increase the potential for drug-drug interactions (pDDIs). This study assessed pDDI prevalence in real-world nmCRPC patients treated with apalutamide, darolutamide, or enzalutamide. RESEARCH DESIGN AND METHODS: Castrated prostate cancer patients without metastases prior to androgen receptor inhibitor initiation were identified retrospectively via Optum Clinformatics Data Mart claims data (8/2019-3/2021). The top 100 concomitant medications were assessed for pDDIs. RESULTS: Among 1,515 patients (mean age: 77 ± 8 years; mean Charlson Comorbidity Index: 3 ± 3), 340 initiated apalutamide, 112 darolutamide, and 1,063 enzalutamide. Common concomitant medication classes were cardiovascular (80%) and central nervous system (52%). Two-thirds of the patients received ≥5 concomitant medications; 30 (30/100 medications) pDDIs were identified for apalutamide and enzalutamide each and 2 (2/100 medications) for darolutamide. Most pDDIs had risk ratings of C or D, but four for apalutamide were rated X. Approximately 58% of the patients on apalutamide, 5% on darolutamide, and 54% on enzalutamide had ≥1 identified pDDI. CONCLUSIONS: Results showed a higher frequency of pDDIs in patients receiving apalutamide and enzalutamide vs darolutamide. The impact of these could not be determined retrospectively. DDI risk should be carefully evaluated when discussing optimal therapy for patients with nmCRPC.
Subject(s)
Androgen Receptor Antagonists , Benzamides , Drug Interactions , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Pyrazoles , Thiohydantoins , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Aged , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/adverse effects , Benzamides/administration & dosage , Benzamides/pharmacology , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/pharmacology , Androgen Receptor Antagonists/adverse effects , Thiohydantoins/administration & dosage , Thiohydantoins/pharmacology , Thiohydantoins/adverse effects , Nitriles/administration & dosage , Aged, 80 and over , Pyrazoles/administration & dosage , Pyrazoles/pharmacology , Pyrazoles/adverse effectsABSTRACT
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.
Subject(s)
Androgen Receptor Antagonists/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/mortality , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Benzamides/therapeutic use , Comorbidity , Humans , Male , Nitriles/therapeutic use , Phenylthiohydantoin/therapeutic use , Pyrazoles/therapeutic use , Quality of Life , Randomized Controlled Trials as Topic , Thiohydantoins/therapeutic useSubject(s)
Androgen Receptor Antagonists/pharmacology , Prostatic Neoplasms/drug therapy , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/metabolism , Humans , Male , Molecular Typing/methods , Molecular Typing/statistics & numerical data , Prostatic Neoplasms/genetics , Signal Transduction/drug effectsABSTRACT
INTRODUCTION: Cabazitaxel multiple rechallenges may be a treatment option in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) who had a good initial response to cabazitaxel and who are still fit to receive it. Our objective was to assess the efficacy and toxicity of multiple rechallenges. PATIENTS AND METHODS: We retrospectively identified 22 mCRPC patients previously treated with docetaxel and/or androgen receptor-targeted agents who received multiple cabazitaxel rechallenges in 9 French centers. Cabazitaxel was initiated at a dose of 25 mg/m2 q3week. A reduced dose (20 mg/m2 q3w) or an alternative schedule (mainly 16 mg/m2 q2w) was increasingly used for subsequent rechallenges. Progression-free survival, prostate-specific antigen (PSA) response, best clinical response, and grade ≥3 toxicities were collected. Overall survival was calculated from various time points. RESULTS: Twenty-two patients with an initial response to cabazitaxel were rechallenged at least twice. The median number of cabazitaxel cycles was 7 at first cabazitaxel treatment, 6 at first rechallenge, and 5 at subsequent rechallenges. Median progression-free survival at first rechallenge was 9.6 months and 5.6 months at second rechallenge. Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life-extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. There was no cumulative grade ≥3 neuropathy or nail disorder and one case of febrile neutropenia. CONCLUSION: Cabazitaxel multiple rechallenges may be a treatment option without cumulative toxicity in heavily pretreated patients having a good response to first cabazitaxel use and still fit to receive it. NOVELTY & IMPACT STATEMENTS: Patients with metastatic castration-resistant prostate cancer can be treated with Cabazitaxel after docetaxel and androgen receptor-targeted agent. This chemotherapy can be used multiple times with efficacy and manageable toxicity.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Taxoids/administration & dosage , Aged , Androgen Receptor Antagonists/administration & dosage , Docetaxel/administration & dosage , Drug Administration Schedule , Follow-Up Studies , Humans , Kallikreins/blood , Kaplan-Meier Estimate , Male , Middle Aged , Progression-Free Survival , Prostate-Specific Antigen/blood , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/mortality , Retrospective StudiesABSTRACT
Background: With hormonal agents quickly expanding as novel therapeutic options in nonmetastatic castration-resistant prostate cancer (nmCRPC), the toxicity profile of enzalutamide, apalutamide, and darolutamide should be kept in mind.Methods: We performed an updated meta-analysis with the aim to analyze the risk of treatment-related cardiovascular (CV) events, any grade, and grade 3-4 (G3-4) hypertension in nmCRPC patients treated with enzalutamide, apalutamide, and darolutamide plus androgen deprivation therapy (ADT) versus ADT plus placebo in randomized controlled trials (RCTs). Results were compared by calculating Relative Risk (RR) with 95% confidence intervals (CIs); RRs were combined with Mantel-Haenszel method.Results: Three RCTs involving 4110 patients were available for the meta-analysis. According to our results, the addition of novel hormonal agents was associated with a significantly increased risk of CV events (RR = 1.71; 95% CI 1.29-2.27) and G3-4 hypertension (RR = 1.53; 95% CI 1.19-1.97). In addition, a trend toward a higher risk of any grade hypertension was reported in the experimental arm.Conclusions: The use of enzalutamide, apalutamide, and darolutamide in nmCRPC patients implies a careful benefit-risk assessment. Real-world, large-cohort studies are warranted to confirm the findings of our meta-analysis.
Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Cardiovascular Diseases/chemically induced , Hypertension/chemically induced , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Antineoplastic Agents, Hormonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cardiovascular Diseases/epidemiology , Humans , Hypertension/epidemiology , Male , Prostatic Neoplasms, Castration-Resistant/drug therapy , Randomized Controlled Trials as TopicABSTRACT
3,5,6-Trichloro-2-pyridinol (TCP) is an important biomarker and one of the final metabolites of chlorpyrifos (CPF). TCP inhibits secretion of sex hormones. Similar to CPF, TCP can bind to sex steroid hormone receptors and decrease the secretion of sex hormones. However, little attention has been paid to the ability of TCP and CPF to interfere with androgen receptor (AR) in Sertoli cells. This study aimed to explain how TCP promotes the inhibitory effect of CPF on the paracrine function of Sertoli cells. Western blotting indicated that after 20 weeks of exposure, expression of AR in testes was significantly reduced by CPF. An in vitro assay measured the cytotoxicity of CPF, TCP and diethylphosphate (DEP) on viability of Sertoli cells by Cell Counting Kit-8. CPF cytotoxicity was greater than that of TCP, and TCP cytotoxicity was greater than that of DEP at concentrations of 1000 µmol/L. Western blotting indicated that TCP and CPF both decreased expression of AR and cAMP-response element binding protein phosphorylation, while DEP had no effect in Sertoli cells, which are important in regulating paracrine function of Sertoli cells. The fluorescence measurements and docking studies revealed that testosterone, CPF and TCP showed four types of intermolecular interactions with AR, highlighting alkyl bonds with some of the same amino acids. Compared with testosterone, CPF and TCP also showed significant synergistic interaction with AR. CPF interacted with more amino acids and interaction energy than TCP did. This research elucidates TCP in the antiandrogenic effect of CPF on the paracrine function and suggests that TCP or chemicals with a trichloropyridine structure must be considered during reproductive toxicity assessment of potential environmental pollutants.
Subject(s)
Androgen Receptor Antagonists/toxicity , Chlorpyrifos/toxicity , Paracrine Communication/drug effects , Pyridones/toxicity , Receptors, Androgen/metabolism , Sertoli Cells/metabolism , Androgen Receptor Antagonists/administration & dosage , Animals , Cell Survival/drug effects , Cell Survival/physiology , Chlorpyrifos/administration & dosage , Dose-Response Relationship, Drug , Drug Synergism , Herbicides/administration & dosage , Herbicides/toxicity , Humans , Insecticides/administration & dosage , Insecticides/toxicity , Male , Paracrine Communication/physiology , Protein Binding/drug effects , Protein Binding/physiology , Pyridones/administration & dosage , Rats , Rats, Sprague-Dawley , Rats, Wistar , Sertoli Cells/drug effectsABSTRACT
INTRODUCTION: Prostate cancer (PC) is the most common cancer in North American men. Advanced PC is incurable. The androgen receptor antagonist enzalutamide is used to manage advanced PC, often over a period of months or years; it is therefore important to evaluate the safety profile of enzalutamide. AREAS COVERED: This literature review presents safety data from pivotal trials and real-world data studies of enzalutamide in patients with advanced PC, including metastatic hormone-sensitive prostate cancer (mHSPC), nonmetastatic castration-resistant prostate cancer (nmCRPC), and metastatic castration-resistant prostate cancer (mCRPC). A large body of evidence supports the maintenance or improvement in the health-related quality of life (HRQoL) afforded by enzalutamide treatment in patients with mHSPC, nmCRPC, or chemotherapy-naïve mCRPC, as well as improvement in the HRQoL in patients with later-stage symptomatic mCRPC. Efficacy data from clinical trials are also briefly discussed. EXPERT OPINION: We aim to provide clinicians with a better understanding of how to properly interpret enzalutamide clinical trial safety data. This knowledge may help clinicians guide their patients with PC to achieve optimal clinical benefit from enzalutamide therapy, and to properly manage their patients to mitigate any potential risk.
Subject(s)
Antineoplastic Agents/administration & dosage , Benzamides/administration & dosage , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms/drug therapy , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Antineoplastic Agents/adverse effects , Benzamides/adverse effects , Humans , Male , Nitriles/adverse effects , Phenylthiohydantoin/adverse effects , Prostatic Neoplasms/pathology , Quality of LifeABSTRACT
Prostate cancer is estimated to be the second most common malignancy in men in the USA in 2020 and represents the second highest mortality from cancer behind lung and bronchial neoplasms. Management of advanced prostate cancer is evolving. Medical androgen deprivation therapy is currently a cornerstone of therapy for prostate cancer; however molecular mechanisms of resistance have emerged leading to castration-resistant prostate cancer that is proliferation of prostate cancer in the setting of low testosterone (< 50 ng/dl). The benefit of double androgen blockade like ADT plus abiraterone acetate or androgen receptor blockers is proven in many clinical trials; however multiple mechanisms of resistance still exist. In theory, another layer of androgen blockade will prevent, or at least slow, prostate cancer proliferation. This direction of thought has recently been explored with multiple clinical trials. In this review article, we summarize the current knowledge regarding androgen resistance, newer androgen inhibition therapies, and the implications of a triple-arm anti-androgen blockade in advanced prostate cancer.
Subject(s)
Androgen Antagonists/administration & dosage , Androgens/metabolism , Antineoplastic Agents/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/metabolism , Androgen Receptor Antagonists/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cell Proliferation/drug effects , Cell Proliferation/physiology , Humans , Male , Neoplasm Invasiveness/pathology , Prostatic Neoplasms, Castration-Resistant/diagnosisABSTRACT
BACKGROUND: Enzalutamide is an orally administered drug that blocks signaling in the androgen receptor with clinical activity in both chemotherapy-naive and post-chemotherapy patients with castrate-resistant prostate cancer (CRPC). Enzalutamide is generally well-tolerated, but dose reductions are nonetheless needed in case of side effects. CASE: An 82-year-old patient with chemotherapy-naive metastatic castration-resistant prostate cancer was treated with a very low dose of 40 mg enzalutamide once daily. The trough levels of enzalutamide and the active metabolite N-desmethylenzalutamide were 4.5 mg/L and 3.0 mg/L, respectively. This exposure provided a long-term response without any significant side effects. CONCLUSION: Low doses of enzalutamide may be efficacious, while also reducing the risk of side effects. Furthermore, employing a lower dose would reduce healthcare costs and increase access to enzalutamide. Studies exploring the efficacy of lower enzalutamide doses are warranted.
Subject(s)
Benzamides/administration & dosage , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Aged, 80 and over , Androgen Receptor Antagonists/administration & dosage , Humans , Male , Receptors, Androgen/metabolismABSTRACT
PURPOSE: No published head-to-head randomized trials have compared the safety and efficacy of darolutamide vs apalutamide or enzalutamide in nonmetastatic castration-resistant prostate cancer. This study compares prespecified adverse events and metastasis-free survival associated with darolutamide vs apalutamide, and darolutamide vs enzalutamide, via matching-adjusted indirect comparisons. MATERIALS AND METHODS: Individual patient data from the phase III ARAMIS trial (NPLACEBO=553; NDAROLUTAMIDE=943) were selected and reweighted to match the inclusion criteria and baseline characteristics published for the phase III SPARTAN (NPLACEBO=401; NAPALUTAMIDE=806) and PROSPER (NPLACEBO=468; NENZALUTAMIDE=933) trials. Only baseline factors consistently reported across trials were included as matching covariates. Both indirect comparisons matched on age, prostate specific antigen level and doubling time, Eastern Cooperative Oncology Group performance status, Gleason score, and bone-sparing agent use. Darolutamide vs apalutamide also matched on prior surgery and darolutamide vs enzalutamide also matched on region. Risk differences and odds ratios were calculated for adverse events and hazard ratios for metastasis-free survival. RESULTS: No differences in metastasis-free survival hazard ratios were found after matching in either comparison. However, fall, fracture and rash rates were statistically significantly lower in favor of darolutamide vs apalutamide. Fall, dizziness, mental impairment, fatigue and severe fatigue rates were statistically significantly lower in favor of darolutamide vs enzalutamide. CONCLUSIONS: While metastasis-free survival did not differ across drugs in these cross-trial indirect comparisons, darolutamide showed a favorable safety and tolerability profile in prespecified adverse events vs apalutamide and enzalutamide. Consideration of these adverse events is important in clinical decision-making and treatment selection in nonmetastatic castration-resistant prostate cancer.
Subject(s)
Benzamides/adverse effects , Nitriles/adverse effects , Phenylthiohydantoin/adverse effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyrazoles/adverse effects , Thiohydantoins/adverse effects , Accidental Falls/statistics & numerical data , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/adverse effects , Benzamides/administration & dosage , Cognitive Dysfunction/chemically induced , Dizziness/chemically induced , Exanthema/chemically induced , Fatigue/chemically induced , Fractures, Spontaneous/chemically induced , Humans , Male , Middle Aged , Nitriles/administration & dosage , Phenylthiohydantoin/administration & dosage , Prostatic Neoplasms, Castration-Resistant/mortality , Pyrazoles/administration & dosage , Thiohydantoins/administration & dosageABSTRACT
Introduction: Important changes in the treatment of prostate cancer have taken place in recent years. Non-metastatic castration-resistant prostate cancer (nmCRPC) has been clinically delineated. In this setting, three drugs have been approved in high-risk disease: apalutamide, enzalutamide and darolutamide.Areas covered:This manuscript aims to profile darolutamide, its clinical development, pharmacologic properties, efficacy and safety. We presented the results of published clinical studies, but we also investigated ongoing ones.Expert opinion: An indirect comparison with the other two aforementioned drugs emerged. While the clinical efficacy is comparable, the toxicity profile is different for darolutamide, resulting in greater tolerance. We must wait for the results of the trials that study darolutamide in hormone-sensitive disease, both in the metastatic phase and in the localized phase. Clinical experience will also be important to determine ever more personalized treatments for patients.
Subject(s)
Androgen Receptor Antagonists/administration & dosage , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyrazoles/administration & dosage , Androgen Receptor Antagonists/adverse effects , Androgen Receptor Antagonists/pharmacology , Animals , Benzamides/administration & dosage , Benzamides/adverse effects , Benzamides/pharmacology , Humans , Male , Nitriles/administration & dosage , Nitriles/adverse effects , Nitriles/pharmacology , Phenylthiohydantoin/administration & dosage , Phenylthiohydantoin/adverse effects , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms, Castration-Resistant/pathology , Pyrazoles/adverse effects , Pyrazoles/pharmacology , Thiohydantoins/administration & dosage , Thiohydantoins/adverse effects , Thiohydantoins/pharmacologyABSTRACT
The biotransformation and excretion of darolutamide were investigated in a phase I study. Six healthy male volunteers received a single dose of 300 mg 14C-darolutamide as an oral solution in the fasted state. Plasma, urine, and feces samples were analyzed for mass balance evaluation by liquid scintillation counting (LSC). Metabolite profiling and identification were determined using liquid chromatography mass-spectrometry with off-line radioactivity detection using LSC. Complete mass balance was achieved, with mean radioactivity recovery of 95.9% within 168 hours (63.4% in urine, 32.4% in feces). The administered 1:1 ratio of (S,R)- and (S,S)-darolutamide changed to approximately 1:5, respectively, in plasma. Darolutamide and the oxidation product, keto-darolutamide, were the only components quantifiable by LSC in plasma, accounting for 87.4% of total radioactivity, with a 2.1-fold higher plasma exposure for keto-darolutamide. Aside from darolutamide, the most prominent metabolites in urine were O-glucoronide (M-7a/b) and N-glucuronide (M-15a/b), as well as pyrazole sulfates (M-29, M-24) and glucuronides (M-21, M-22) resulting from oxidative cleavage of the parent. The darolutamide diastereomers were mainly detected in feces. In vitro assays showed that darolutamide metabolism involves a complex interplay between oxidation and reduction, as well as glucuronidation. Interconversion of the diastereomers involves oxidation to keto-darolutamide, primarily mediated by CYP3A4, followed by reduction predominantly catalyzed by cytosolic reductase(s), with aldo-keto reductase 1C3 playing the major role. The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide. SIGNIFICANCE STATEMENT: The metabolism and excretion of darolutamide in humans revealed that oxidation (CYP3A4) and glucuronidation (UGT1A9, UGT1A1) were the main metabolic routes of elimination. Direct excretion also contributed to overall clearance. The two pharmacologically equipotent diastereomers of darolutamide interconvert primarily via oxidation to the active metabolite keto-darolutamide, followed by reduction predominantly by cytosolic reductase(s). The latter reaction showed stereoselectivity with preferential formation of (S,S)-darolutamide. Data indicate a low drug-drug interaction potential of darolutamide with inducers or inhibitors of metabolizing enzymes.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Drug Elimination Routes/physiology , Glucuronides , Pyrazoles , UDP-Glucuronosyltransferase 1A9/metabolism , Adult , Androgen Receptor Antagonists/administration & dosage , Androgen Receptor Antagonists/pharmacokinetics , Biotransformation , Glucuronides/metabolism , Glucuronides/urine , Healthy Volunteers , Humans , Male , Mass Spectrometry/methods , Oxidation-Reduction , Pharmaceutical Solutions/administration & dosage , Pharmaceutical Solutions/pharmacokinetics , Pyrazoles/administration & dosage , Pyrazoles/pharmacokinetics , Scintillation Counting/methodsABSTRACT
Background: Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Results: Median overall survival (OS) from the start of first-line treatment was 39.8 months, with the patients who completed all six planned courses of RA223 having a longer OS than those who did not (53.2 vs 29.5 months; p < 0.0001). Conclusions: Our study confirms the activity of RA223 regardless of the treatment line in which it is administered and suggests that patient selection plays a central role in maximizing this activity.
Subject(s)
Androgen Receptor Antagonists/administration & dosage , Bone Neoplasms/therapy , Prostatic Neoplasms, Castration-Resistant/therapy , Radiopharmaceuticals/administration & dosage , Radium/administration & dosage , Aged , Aged, 80 and over , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Chemoradiotherapy/methods , Follow-Up Studies , Humans , Italy/epidemiology , Male , Middle Aged , Neoplasm Grading , Patient Selection , Prostatectomy , Prostatic Neoplasms, Castration-Resistant/diagnosis , Prostatic Neoplasms, Castration-Resistant/mortality , Prostatic Neoplasms, Castration-Resistant/pathology , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
INTRODUCTION: Prostate cancer progresses, despite androgen-deprivation therapy, the backbone of its treatment. This progression is mainly related to the androgen receptor (AR)-related mechanisms of resistance, and, several AR-targeted therapies have demonstrated benefit in metastatic and nonmetastatic disease. Apalutamide is a third-generation AR-targeted therapy which competitively blocks the AR and prevents AR dimerization, nuclear internalization, thereby avoiding cancer progression. Early studies have demonstrated that apalutamide was safe and demonstrated clinical benefit. Phase II and phase III studies had confirmed preliminary results of clinical benefit with apalutamide in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) and in metastatic hormone-sensitive prostate cancer (mHSPC). AREAS COVERED: Herein, the authors discuss the development of apalutamide, from its discovery and early studies to phase III trials. They also examine new perspectives and biomarkers that may help oncologists to make decisions in patients taking apalutamide. Studies evaluating apalutamide in other settings and in combination with other therapies are also debated. EXPERT OPINION: Apalutamide has become a relevant therapy for patients with nmCRPC and mHSPC for its benefit in delaying metastasis in addition to its improvement of overall survival, without compromising the quality of life. Apalutamide should be considered as a standard-of-care for patients with nmCRPC and patients with mHSPC.
Subject(s)
Androgen Receptor Antagonists/administration & dosage , Prostatic Neoplasms/drug therapy , Thiohydantoins/administration & dosage , Androgen Receptor Antagonists/pharmacology , Biomarkers, Tumor/metabolism , Drug Development , Humans , Male , Prostatic Neoplasms/pathology , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Quality of Life , Survival Rate , Thiohydantoins/pharmacologyABSTRACT
PURPOSE: Enzalutamide (ENZ) is an androgen receptor inhibitor used for the treatment of castration-resistant prostate cancer (CRPC). The aim of this study was to evaluate the safety of the ENZ by dose-escalation strategy in patients with CRPC. METHODS: We retrospectively reviewed patients with CRPC who received standard ENZ (started at 160 mg) or dose-escalation ENZ (started at 80 mg followed by dose escalation) from May 2014 to June 2019 in our hospital. Safety and time to treatment failure (TTF) were evaluated. Multivariate logistic regression analysis was used to evaluate adverse events and drug discontinuation. Multivariate Cox regression analysis was used to evaluate TTF. RESULTS: Among 107 patients, 17 patients received standard ENZ and 90 patients received dose-escalation ENZ therapy. Adverse events (any grade) were observed in 88.2% of patients in the standard group and 63.3% in the dose-escalation group (Pâ¯=â¯0.020). Grade ≥3 adverse events were observed in 23.5% and 6.7% of the patients in the standard and dose-escalation groups, respectively, (Pâ¯=â¯0.021). Discontinuation due to adverse events was 35.3% and 12.2% in the standard and dose-escalation groups, respectively (Pâ¯=â¯0.070). Median TTF was 10.4 months (95% confidential interval [CI]: 2.6-31.3 months) and 18.0 months (95% CI: 11.5-22.8 months) in the standard and dose-escalation groups, respectively (Hazard ratio: 0.60, 95% CI: 0.29-1.30, Pâ¯=â¯0.194). CONCLUSIONS: With the ENZ dose-escalation strategy, adverse events related to ENZ of any grade and grade ≥3 were significantly decreased, and discontinuation due to adverse events also decreased. Therefore, the dose-escalation strategy could be useful in optimizing the dose of ENZ.