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Urological Anti-cancer Agents
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Bernadett Szabados, Thomas Powles
ApalutamideNovel anti-androgen that is closely related to enzalutamide.Binds to the same ligand-binding site as bicalutamide.But has a 7–10-fold higher affinity for the AR.Side effects: rash, hypothyroidism, increased risk of pathological bone fracture.
Therapeutic Options for Prostate Cancer: A Contemporary Update
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sakthivel Muniyan, Jawed A. Siddiqui, Surinder K. Batra
A recent phase III clinical trial showed that ADT plus Apalutamide (Erleada) was found to significantly associate with radiographic PFS (rPFS) and OS versus placebo in metastatic CSPCa settings. SPARTAN phase III study which randomized 1207 patients in a 2:1 ratio already revealed that addition of ADT led reduced risk of metastasis (72%) and death in nonmetastatic CRPC patients. This trial shows that apalutamide significantly increases median metastasis-free survival [40.5 months vs. 16.2 months (HR = 0.28, 0.23 to 0.35; P<0.001)]. Similarly, the apalutamide treatment significantly extends the time to symptomatic progression (HR = 0.45; 0.32 to 0.63; P<0.001) [31]. Similarly, unpublished Phase 3 TITAN study from Janssen Pharmaceuticals describes that apalutamide achieved primary endpoint in metastatic CSPCa. [115].
Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Interestingly, the acquired F876L mutation of the AR identified in some advanced prostate cancer cells has been shown to confer resistance to both apalutamide and enzalutamide. The newer NSAA, darolutamide, is not affected by this mutation, nor is it affected by any other known AR mutations. Also, apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.
Current androgen receptor antagonists under investigation for resistant prostate cancer
Published in Expert Review of Anticancer Therapy, 2022
Maria Concetta Nigro, Veronica Mollica, Andrea Marchetti, Michael Cheng, Matteo Rosellini, Rodolfo Montironi, Liang Cheng, Francesco Massari
Apalutamide (Erleada®) was shown to be effective in mCRPC at daily dose of 240 mg, with the 47% PSA response in a phase I clinical trial [34,35]. It is approved for high-risk nmCRPC based on the results of the SPARTAN trial, a randomized, double blind and multicenter phase III study, which randomized 1207 patients with nmCRPC to receive apalutamide plus ADT vs placebo plus ADT. After a second interim analysis, the resulting data confirmed a benefit in median MFS (40.5 months vs 16.2 months, HR 0.28), an improvement over time to symptomatic progression and a significance reduction for risk of death, compared to the control group [36]. The most common adverse events of apalutamide were rash and fatigue, moderately hypertension, hot flashes, arthralgia, diarrhea and weight loss [36].
An evaluation of apalutamide for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2020
Myrto Boukovala, Nicholas Spetsieris, Eleni Efstathiou
Apalutamide is an orally available drug with a recommended dose of 240 mg daily. Following repeated dosing of 30–480 mg once daily, apalutamide Cmax and area under the concentration curve (AUC) increased proportionally. Steady state was reached after 3 weeks of continuous administration. After administration of the recommended dose, mean steady state Cmax is 7.6 μg.h/mL and AUC0-24hours is 127 μg.h/mL. Mean absolute oral bioavailability is approximately 100% and mean time to achieve peak plasma concentration following administration of the recommended dose is 3.5 hours. No differences in Cmax and AUC were observed between dosing in a fasting state or after a high-fat meal. Apalutamide as well as the active metabolite N-desmethyl apalutamide are 95–96% bound to plasma proteins. The drug’s half-life is approximately 3 days at steady state. Elimination is achieved through metabolism by CYP2C8 and CYP3A4 and excretion is renal (65%) and fecal (24%) [29,30].
Investigational therapies targeting the androgen signaling axis and the androgen receptor and in prostate cancer – recent developments and future directions
Published in Expert Opinion on Investigational Drugs, 2018
Pedro Isaacsson Velho, Michael A. Carducci
Apalutamide (ARN-509) is a second-generation antiandrogen which binds AR with 7- to 10-fold greater affinity than the clinically approved antiandrogen bicalutamide. The drug has a similar structure to enzalutamide, however, demonstrated a greater in vivo activity per unit dose and per unit steady-state plasma level in CRPC xenograft mouse models as compared to enzalutamide [11]. The phase I trial which evaluated apalutamide enrolled 30 patients to receive different doses of the drug [12]. The objectives of the study were to evaluate pharmacokinetics, safety, tolerability, and to define a recommended phase II dose. The study showed that the most frequent adverse events (AEs) were fatigue (47%), back pain (30%), diarrhea (30%), and nausea (30%), demonstrating that the drug was safe and well tolerated. Apalutamide demonstrated anticancer activity, showing 60% (18/30) of PSA50 (prostate-specific antigen) response (PSA decline ≥50%) and 20% (6/30) of PSA90 response (PSA decline ≥90%). Based on the safety and efficacy, the dose selected for phase II trials was 240 mg daily.