New (Wednesday) Phase 3 paper in the NEJM [1].
Darolutamide (previously known as ODM-201) is an androgen receptor [AR] antagonist. How does it differ from Enzalutamide (Xtandi) & Apalutamide (Erleada) (previously: ARN-509), say? {Skip to "New study" if not interested.}
From 2015 [2]:
"Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC."
***
New study:
"We conducted a randomized, double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic, castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned in a 2:1 ratio to receive darolutamide (600 mg [two 300-mg tablets] twice daily) or placebo while continuing androgen-deprivation therapy. The primary end point was metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks."
"In total, 1509 patients underwent randomization (955 to the darolutamide group and 554 to the placebo group). In the planned primary analysis, which was performed after 437 primary end-point events had occurred, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo (hazard ratio for metastasis or death in the darolutamide group, 0.41 ..."
The link below [1] is to the full text.
For those interested, the Discussion section is pasted here:
"Darolutamide is a nonsteroidal androgen-receptor antagonist that is structurally distinct from other androgen-receptor inhibitors, consisting of two pharmacologically active diastereomers.14 In our trial, darolutamide prolonged metastasis-free survival to 40.4 months, 22 months longer than with placebo. The risk of metastasis or death from any cause was reduced by 59%, and the benefit was consistent across all subgroups, including the subgroup of patients with lower-risk disease. The results for the secondary end point of overall survival also favored darolutamide, although the prespecified alpha split between the primary and the final analysis prevented the significance criteria from being met in this analysis. The results with regard to all secondary end points supported that of the primary end point, and consistent efficacy was observed for metastasis-free, overall, and progression-free survival.
"The median metastasis-free survival with darolutamide in the current trial is similar to that in two previous randomized, controlled trials involving patients with nonmetastatic, castration-resistant prostate cancer. The median metastasis-free survival was 36.6 months with enzalutamide (vs. 14.7 months with placebo) in the PROSPER phase 3 trial and was 40.4 months with apalutamide (vs. 16.2 months with placebo) in the SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) phase 3 trial.10,11 Fatigue and asthenia, which are common adverse events in patients receiving hormone-targeted therapy for advanced prostate cancer, were less common in the current trial than in the PROSPER or SPARTAN trial.10,11 In contrast to apalutamide and enzalutamide, darolutamide was not associated with a higher incidence of falls or fractures than placebo,10,11 despite few patients using osteoclast-targeted therapies. Seizures were noted as a potential risk in the dose-escalation and toxicity studies of enzalutamide,24 whereas the preclinical and clinical data for darolutamide did not indicate any proconvulsive potential.19 Patients with a history of seizure were therefore allowed to enter the trial, in contrast to the SPARTAN and PROSPER trials. The incidence of seizure events was low and similar in the darolutamide and placebo groups (Table 3); none of the patients with a medical history of seizure (12 in the darolutamide group) had a seizure during the trial. The incidences of rash and hypothyroidism, which were higher among patients receiving apalutamide than among those receiving placebo,10 were low and similar in the darolutamide and placebo groups, as were the incidences of hypertension and central nervous system (CNS)–related adverse events. In the PROSPER and SPARTAN trials, hypertension and CNS-related adverse effects, such as mental-impairment disorders and dizziness, were more common among patients receiving enzalutamide or apalutamide than among those receiving placebo.10,11 The similar incidences of seizures, dizziness, and cognitive impairment in the darolutamide and placebo groups in the current trial may be linked to the low penetration of the blood–brain barrier that has been found in preclinical studies of the drug.13
"These results confirm the benefits of early and potent inhibition of androgen-receptor signaling in patients with nonmetastatic, castration-resistant prostate cancer.25 Other trials, such as the LATITUDE and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trials of abiraterone added to androgen-deprivation therapy in patients with castration-sensitive prostate cancer, have similarly confirmed that early inhibition of androgen-receptor signaling offers significant survival benefits to patients.26,27 In addition to survival benefit, quality of life is also an important factor in making treatment choices for patients with nonmetastatic, castration-resistant prostate cancer,28 since it can be negatively affected by adverse events resulting from therapies and medical interventions as well as from symptomatic disease progression. In the current trial, darolutamide treatment did not adversely affect quality of life, and it resulted in delayed occurrence of metastases with a favorable safety profile.
"This trial has several strengths. The large size enabled a robust statistical analysis as well as the detection of rare but important safety signals. Patients’ quality of life was assessed in detail with the use of validated instruments to assess different aspects of the effect of treatment, including the BPI scale to measure pain progression. A limitation of the trial is the underrepresentation of patients of African descent (52 in total); therefore, no conclusions can be drawn about efficacy in this group. In addition, treatment with subsequent life-prolonging therapy after the onset of metastases in the placebo group could potentially affect the observed relative benefits of darolutamide with regard to secondary end points. The percentages of patients who received subsequent treatment are lower than those reported in the SPARTAN trial, in which the trial design included the provision of abiraterone for patients in whom metastases developed.
"In conclusion, metastasis-free survival was significantly longer with darolutamide than with placebo for men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less. The results for the secondary and exploratory end points supported the benefits of darolutamide in this clinical context. The safety data indicated no clinically relevant difference between darolutamide and placebo in the incidence of adverse events that occurred during the treatment period, including falls, fractures, seizures, cognitive disorders, and hypertension. Quality-of-life outcomes were similar in the two groups."
-Patrick
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