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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Approval by the FDA was based on a multicenter, double-blinded, placebo-controlled clinical trial (ARAMIS) in 1,509 patients who had either received a GnRH analog concurrently or otherwise had been orchiectomized. The median Metastasis-Free Survival (MFS) was 40.4 months for patients treated with darolutamide compared with 18.4 months for those receiving placebo. For some patients, a reduction in PSA levels of more than 90% was achieved. Darolutamide is also being studied for the treatment of breast cancer in women, and was in Phase II clinical trials for this indication in 2019.
An up-to-date evaluation of abiraterone for the treatment of prostate cancer
Published in Expert Opinion on Pharmacotherapy, 2021
Jason Shpilsky, Julia Stevens, Glenn Bubley
Apalutamide, a novel androgen receptor antagonist, is approved for nonmetastatic castration-resistant prostate cancer (nmCRPC) and mCSPC. While it carries the typical effects of this drug class (hot flashes, fatigue, hypertension), unique side effects include hypothyroidism, rash, falls, and a low risk of seizure [5]. Enzalutamide is an androgen receptor antagonist approved for all three indications: nmCRPC, mCSPC, and mCRPC. Enzalutamide carries a risk of cognitive impairment, falls, and seizures in addition to the class effects [6]. Finally, darolutamide is an androgen receptor antagonist approved only for nmCRPC. Darolutamide is distinguished by its low brain penetration and therefore lower fatigue, cognitive impairment, and seizure risk compared to other drugs in this class [7].
Darolutamide in hormone-sensitive and castration-resistant prostate cancer
Published in Expert Review of Clinical Pharmacology, 2021
Valeria Emma Palmieri, Giandomenico Roviello, Alberto D’Angelo, Chiara Casadei, Ugo De Giorgi, Roberta Giorgione
The efficacy of darolutamide in prostate cancer was initially evaluated in phase 1–2 studies (Table 1). The ARADES trial was an open-label phase 1–2 trial that assessed safety, tolerability, and efficacy of darolutamide in men with progressive mCRPC, with the phase 1 consisting of a non-randomized dose-escalation cohort while the phase 2 including a randomized dose-expansion cohort. During phase 1, the PSA response (defined as ≥50% decrease of serum PSA from baseline) was achieved by 81% of patients at week 12. In phase 2, patients were randomly assigned to receive one of three daily doses of darolutamide (200 mg, 400 mg, and 1400 mg). Within the phase 2 dose-expansion component, 11 patients (29%) from the 200 mg group,13 (33%) from the 400 mg group and 11 (33%) from the 1400 mg group had a PSA response at 12 weeks. Darolutamide activity was equally observed between all different doses administered. Stratifying patients into three groups, according to previous regimens received (chemotherapy-naive and CYP17 inhibitor-naïve, post-chemotherapy and CYP17 inhibitor-naïve, post-CYP17 inhibitor), the PSA response was significantly lower (7% in the 1400 mg group) in patients previously treated with CYP17 inhibitors than in those who were naïve for both chemotherapy and CYP17 inhibitors (86% in the 1400 mg group), and those who previously received chemotherapy alone (36% in the 1400 mg group) [29].
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
The first study which evaluated darolutamide was the ARADES trial, which had two portions: a phase I dose-escalation trial and a phase II randomized dose expansion [17]. In the phase I part of this study, patients with mCRPC were included to receive darolutamide at a starting daily dose of 200 mg, which was increased to 400 mg, 600 mg, 1000 mg, 1400 mg, and 1800 mg. The phase II part included three different dose cohorts: (1) 200 mg, (2) 400 mg, and (3) 1400 mg daily. All patients had received at least one first-generation antiandrogen and up to two previous chemotherapy regimens. Altogether 136 patients were enrolled (24 in the first part and 112 in the second part). Darolutamide was well-tolerated, being the majority (93%) of the side effects grade 1 or 2, and the maximum tolerated dose was not reached. The most common AEs in the dose-escalation trial were fatigue (42%), diarrhea (29%), arthralgia (25%), back pain (25%), and headache (21%). Grade 3 AEs were seen in 13% of patients (fracture, muscle injury, paralytic ileus, pain, pre-syncope, urinary retention, and vomiting) and grade 4 was seen in 1 patient only (lymphedema).