Digital Features for this AdisInsight Report can be found at https://doi.org/10.6084/m9.figshare.22591285.

FormalPara Darolutamide: clinical considerations in metastatic HSPC

Oral ARi, approved for triple therapy with ADT and docetaxel

Significantly extended overall survival versus placebo (plus ADT and docetaxel) in a pivotal trial

Manageable tolerability profile with adverse events generally consistent with those previously reported for ADT and docetaxel

1 Introduction

Prostate cancer is among the most diagnosed types of cancer in the USA and Europe [1, 2]. Prostate cancer was estimated to be the second most diagnosed cancer in 2023 (288,300 new cases) in the USA and the fourth most diagnosed in Europe in 2020 (473,000 new cases) [1, 2]. Based on US data, distant or regional metastases were detected at first presentation in 8% and 13% of patients, respectively [1]. In patients who have distant metastatic disease, 5-year survival rates are 34.1% versus 100% survival reported for patients with localised or regional disease [1]. Furthermore, patients who present with de novo metastatic disease are more likely to have indicators of aggressive disease (e.g. higher prostate-specific antigen levels) and worse survival outcomes than patients with primary progressive disease [3].

For patients with metastatic hormone-sensitive (castration-sensitive) prostate cancer (mHSPC), androgen-deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH)/gonadotropin-releasing hormone (GnRH) agonist or antagonist was the historical gold standard treatment in this indication [4]. The addition of docetaxel was subsequently established as a treatment option for more severe, high-volume metastatic disease, which is typically defined as the presence of visceral metastases and/or ≥ 4 bone metastases with spread beyond the pelvis and vertebral column [4, 5]. More recently, the addition of an androgen receptor inhibitor (ARi) to ADT as double therapy, or triple therapy with an ARi, ADT and docetaxel, have been used for the treatment of mHSPC [6,7,8,9,10].

Darolutamide (NUBEQA®) is an oral ARi, which has been approved in combination with ADT and docetaxel for the treatment of mHSPC in the USA [11], the EU [12], Japan [13] and China [14]. This article reviews the clinical data of darolutamide for the treatment of mHSPC in the USA and the EU. The pharmacological properties of darolutamide are summarised in Table 1. Its use in the treatment of non-metastatic castration-resistant prostate cancer was previously reported [15], and discussion of this indication is outside the scope of this article.

Table 1 Pharmacological properties of darolutamide
Full size table

2 Therapeutic Efficacy of Darolutamide

The therapeutic efficacy of darolutamide in combination with ADT and docetaxel was evaluated in the randomized, double-blind, multinational ARASENS phase III trial [16]. Patients aged ≥ 18 years with metastatic prostate cancer who were candidates for treatment with ADT and docetaxel and who had an Eastern Cooperative Oncology Group (ECOG) performance status score 0–1 (scale 0–5, with higher scores corresponding to greater disability) were eligible for enrolment. A diagnosis of prostate cancer was histologically or cytologically confirmed and metastases were detected by conventional imaging techniques (e.g. magnetic resonance imaging). Main exclusion criteria included disease which was confined to regional lymph nodes (N1, below the aortic bifurcation), treatment with ADT > 12 weeks prior to randomization, or treatment with a second-generation ARi, chemotherapy, immunotherapy or radiotherapy < 2 weeks prior to randomization [16].

All patients in the trial received treatment with LHRH-based ADT (or an orchiectomy) and docetaxel in addition to study treatment [i.e. darolutamide or placebo] (Fig. 1) [16]. Patients were randomized to receive darolutamide 600 mg or placebo (hereafter referred to as the darolutamide and placebo groups, respectively), taken twice daily with food. Treatment was continued until symptomatic disease progression, a change in antineoplastic therapy, intolerable toxicity, withdrawal of consent, physician or investigator decision, nonadherence or death [16].

Fig. 1
figure 1

Trial design of the randomized, double-blind, multinational phase III ARASENS trial in adults with metastatic hormone-sensitive prostate cancer [16]. Efficacy results are reported in the animated figure (available online). ADT androgen deprivation therapy, bid twice daily, HR hazard ratio, NE not estimable. a1305 patients were included in the full analysis set

Full size image

Patient baseline characteristics and demographics were generally balanced across the darolutamide and placebo treatment groups [16]. The median age was 67 years in both treatment groups. Parameters relating to disease severity at initial diagnosis were generally consistent across treatment groups; including Gleason score [scale 6–10, higher scores indicating more aggressive disease] (77.6% and 78.9% of patients had a score ≥ 8) and metastasis stage (M1, distant metastasis in 85.7% and 86.5% of patients). Median serum prostate-specific antigen levels were 30.3 and 24.2 ng/mL and median alkaline phosphatase levels were 148 and 140 U/L in the respective treatment groups [16].

The primary endpoint of the trial was overall survival (OS), which was evaluated after 533 deaths had occurred (229 and 304 patients in the darolutamide and placebo groups) [16]. Patients were assessed every 12 weeks for safety and other endpoints (e.g. evidence of castration-resistant disease). Imaging of the chest, abdomen and pelvis was performed at baseline, ≤ 30 days after the last cycle of docetaxel and once yearly thereafter in patients receiving study treatment [16].

Treatment with darolutamide, ADT and docetaxel was associated with a significantly lower risk of death in comparison with placebo, ADT and docetaxel (Table 2) [16]. Four-year survival rates in the darolutamide and placebo treatment groups were 62.7% (95% CI 58.7%–66.7%) and 50.4% (95% CI 46.3%–54.6%). Subgroup analyses of the OS data, including in subgroups based on demographics and indicators of disease severity (e.g. ECOG or Gleason scores and metastasis stage), indicated that treatment effects observed in the subgroups were generally consistent with those reported in the overall trial population [16].

Table 2 Efficacy of darolutamide in combination with androgen deprivation therapy and docetaxel in patients with metastatic hormone-sensitive prostate cancer
Full size table

Darolutamide was superior to placebo for the first five secondary endpoints tested hierarchically, including time to castration-resistant disease and time to pain progression (Table 2) [16]. There was, however, no significant between-group difference in the time to worsening of disease-related physical symptoms. An exploratory analysis indicated a potential benefit in the time to initiating opioids for ≥ 7 days with darolutamide over placebo (Table 2) [16].

In a post-hoc analysis, the improvement in OS with darolutamide versus placebo in the overall trial population was generally consistent to that observed in subgroups based on disease volume or risk [5]. High-volume disease was defined as the presence of visceral metastases and/or ≥ 4 bone metastases with ≥ 1 metastases beyond the vertebral column and pelvis. High-risk disease was defined as the presence of any two of the following risk factors, Gleason score ≥ 8, ≥ 3 bone metastases or measurable visceral metastasis. In patients with high-volume versus low-volume disease, the hazard ratios (HR) of the OS with darolutamide compared with placebo were 0.69 (95% CI 0.57–0.82) versus 0.68 (95% CI 0.41–1.13) in the respective subgroups. Similar benefits were also observed across the high-risk (HR 0.71; 95% CI 0.58–0.86) and low-risk (HR 0.62; 95% CI 0.42–0.90) disease subgroups [5].

Darolutamide treatment did not appear to impair quality of life (QoL) [17]. High baseline QoL scores were maintained in most patients during the trial (the scores were not reported). Furthermore, the time-to-worsening was comparable between the darolutamide and placebo groups [17].

3 Tolerability of Darolutamide

Darolutamide, in combination with ADT and docetaxel, had a manageable tolerability profile in patients enrolled in the ARASENS trial (Sect. 2) [16]. The safety analysis set included 652 and 650 patients in the darolutamide and placebo treatment groups, respectively. Adverse events (AEs) were reported in almost all patients in the darolutamide and placebo treatment groups (99.5% vs 98.9%, respectively). The most common AEs (incidence ≥ 20% in either treatment group) were alopecia (40.5% vs 40.6%), neutropenia (39.3% vs 38.8%), fatigue (33.1% vs 32.9%), anaemia (27.8% vs 25.1%), arthralgia (27.3% vs 26.8%), peripheral oedema (26.5% vs 26.0%), diarrhoea (25.6% vs 24.0%) and constipation (22.5% vs 20.0%). AEs related to ADT or ARis with an incidence ≥ 10% were fatigue (33.1% vs 32.9%), vasodilatation and flushing (20.4% vs 21.7%), rash (16.6% vs 13.5%), diabetes mellitus and hyperglycaemia (15.2% vs 14.3%), hypertension (13.7% vs 9.2%) and cardiac disorder (10.9% vs 11.7%) [16]. In a post-hoc analysis, the incidences of serious AEs between the darolutamide and placebo treatment groups were generally consistent across subgroups of patients with high-volume (45.4% vs 43.5%), low-volume (42.9% vs 38.2%), high-risk (45.3% vs 42.9%) and low-risk (43.7% vs 40.9%) disease [5].

The most common adverse drug reactions (ADRs) [incidence ≥ 10% and ≥ 2% higher in the darolutamide than the placebo group] were constipation, decreased appetite, rash, haemorrhage, weight increase and hypertension (Fig. 2) [11]. Rarer, but nonetheless clinically significant, ADRs included fractures (8% vs not reported, in the darolutamide and placebo groups, respectively), ischaemic heart disease (2.9% vs 2.0%), seizures (0.6% vs 0.2%) and drug-induced liver injury (0.3% vs not reported) [11].

Fig. 2
figure 2

Adverse drug reactions occurring with an incidence of ≥ 10% and ≥ 2% higher in the darolutamide group versus the placebo group [11]. ADT androgen deprivation therapy, ADRs adverse drug reactions

Full size image

Dosage interruption, dosage reduction or permanent discontinuation of darolutamide due to ADRs occurred in 23%, 9% and 14% of patients in the darolutamide group, respectively (the incidences were not reported for the placebo group) [11]. The most common (incidence ≥ 2%) ADRs for dosage interruption of darolutamide were alanine aminotransferase (ALT) increased (3.2%), aspartate aminotransferase (AST) increased (3.1%) and febrile neutropenia (2.1%); ALT increased (2.8%) and AST increased (2.5%) were the most common ADRs associated with dosage reduction of darolutamide. The incidences of individual ADRs associated with permanent discontinuation of darolutamide were all < 1% [11].

Serious ADRs were reported in 45% versus 42% of patients in the darolutamide and placebo groups, respectively [11]. The most common (incidence ≥ 2%) serious ADRs reported in the darolutamide group were febrile neutropenia (6%), neutrophil count decreased (2.8%), musculoskeletal pain (2.6%) and pneumonia (2.6%); the incidences were not reported in the placebo group. Fatal ADRs were reported in 4% of patients in both treatment groups [11].

4 Dosage and Administration of Darolutamide

The recommended dosage of darolutamide in the USA and the EU for the treatment of mHSPC is 600 mg taken twice daily with food [11, 12]. Concurrent treatment with GnRH/LHRH-based ADT (or a bilateral orchiectomy) and six cycles of docetaxel, initiated within 6 weeks of starting darolutamide treatment, is required. Darolutamide treatment may be continued until unacceptable toxicity or disease progression, irrespective of interruption or discontinuation of treatment with docetaxel [11, 12].

The dosage of darolutamide may be reduced to 300 mg taken twice daily or treatment may be temporarily withheld in patients experiencing grade ≥ 3 or intolerable ADRs [11, 12]. Similarly, due to the potential for increased darolutamide exposure (Table 1), the dosage may be reduced to 300 mg twice daily in patients with an estimated glomerular filtration rate 15–29 mL/min/1.73 m2 who are not receiving haemodialysis or in patients with moderate (Child-Pugh Class B) hepatic impairment in the USA [11] or moderate to severe (Child-Pugh Class B or C) hepatic impairment in the EU [12]. Dosage reductions below 300 mg twice daily are not recommended for both regions [11, 12].

In the USA and the EU, the use of contraception during treatment and for one week after treatment is recommended in men who have female partners of reproductive potential as darolutamide can cause foetal harm and loss of pregnancy (Table 1) [11, 12]. The use of darolutamide is contraindicated in women who are pregnant or may become pregnant in the EU [12].

In the EU, close monitoring for ADRs in patients with kidney disease or hepatic impairment is recommended due to the potential for increased darolutamide exposure in these patients (Table 1) [12]. Other warnings include an ADT-related class warning regarding a potential for prolongation of QT interval, and the fact that the safety of darolutamide has not been established in patients with recent cardiovascular disease. Cases of drug-induced liver injury have been reported (Sect. 3); permanent discontinuation of darolutamide is recommended in these patients [12].

In the USA, monitoring patients for signs and symptoms of ischaemic heart disease, in addition to optimizing the management of cardiovascular risk factors, is recommended [11]. Additionally, seizures have been reported during darolutamide treatment (Sect. 3); treatment may be discontinued in patients who develop seizures [11]. Consult local prescribing information for details regarding dosage, additional warnings or precautions and contraindications.

5 Place of Darolutamide in the Management of Prostate Cancer

Treatment with darolutamide plus ADT and docetaxel as triple therapy was effective (Sect. 2) and had a manageable tolerability profile (Sect. 3) in patients with mHSPC during the pivotal ARASENS phase III trial [16]. The OS was significantly prolonged with darolutamide-based triple therapy (i.e. darolutamide plus ADT and docetaxel) versus placebo plus ADT and docetaxel, and improvements were observed across most secondary endpoints (Sect. 2). The types and incidences of the most common AEs reported with darolutamide-based triple therapy were generally consistent with those reported for placebo plus ADT and docetaxel during ARASENS, although, some ADRs were observed with a ≥ 2% higher incidence in the darolutamide group (Sect. 3). Furthermore, the most common AEs were generally consistent with the known toxicity profile of docetaxel [16]. Dose reduction or temporary discontinuation of darolutamide are permitted to manage grade ≥ 3 or intolerable ADRs (Sect. 4).

In light of interest in the treatment of high-volume mHSPC with darolutamide plus ADT and docetaxel, a post-hoc analysis of ARASENS indicated that the relative benefits in OS of darolutamide versus placebo were generally consistent (and similar to that in the overall trial population) across disease volume and risk subgroups, including in patients with high-volume disease (Sect. 2) [5]. Notably, the separation of the survival curve between darolutamide and placebo occurred later in the trial for patients with low-volume disease, potentially reflecting the better underlying prognosis for patients in this subgroup. Additionally, the smaller size of this subgroup (23% of the patients in the trial) may have contributed towards the inclusion of 1 within the range of the 95% CI. The incidence rates of serious AEs were also generally consistent between the darolutamide and placebo treatment groups across disease volume and risk subgroups (Sect. 3) [5].

Darolutamide is recommended as a treatment option for mHSPC in North American guidelines [6, 7]. The US National Comprehensive Cancer Network recommends darolutamide in combination with ADT and docetaxel as a preferred treatment option for the treatment of mHSPC, particularly for patients who have high-volume disease and are candidates for chemotherapy [6]. The Canadian Urological Association recommends systemic triple therapy in patients who can safely tolerate docetaxel and if docetaxel treatment is appropriate [7]. Treatment with darolutamide plus ADT and docetaxel is recommended for mHSPC regardless of disease volume, as the effect of disease volume in ARASENS was reported after the publication of these guidelines [7]. Data consistent with this recommendation are available from a posthoc analysis [5]. European guidelines by the European Society for Medical Oncology recommend darolutamide plus ADT and docetaxel as a first line therapy in patients who have mHSPC, including in patients who have de novo or progressive mHSPC [9]. The European Association of Urology recommends either darolutamide or abiraterone in combination with ADT and docetaxel only in patients who have M1 mHSPC and are fit for treatment with docetaxel [10].

Network meta-analyses were inconclusive in establishing the relative benefit of darolutamide triple therapy in comparison with other triple therapies or ADT plus ARi double therapies in patients with mHSPC [18,19,20,21]. For example, darolutamide triple therapy was ranked first for improvements in OS in comparison with other triple therapies or double therapies in two analyses, although statistical significance was not reached for the differences between the treatment groups [18, 20]. Darolutamide triple therapy was, however, superior to ADT monotherapy [20] or ADT plus docetaxel [18, 19] across all analyses with respect to OS. One analysis suggested the benefit-risk ratio favours ADT plus ARi double therapy over triple therapies due to the lower incidence of grade ≥ 3 AEs, although these results are based on uncertain estimates of AEs [19]. In another analysis of AEs, darolutamide triple therapy was not associated with a higher incidence of grade ≥ 3 AEs versus ADT plus docetaxel, except for hypertension (odds ratio 2.08; 95% CI 1.23–3.63) [18]. Lastly, a meta-analysis that stratified patients by disease volume indicated that triple therapies were most effective in treating patients with high-volume disease, whereas ARi double therapies were generally most effective in patients with low-volume disease [21]. Notably, in patients with high-volume disease, darolutamide triple therapy was ranked highest for efficacy and was associated with a significant benefit in OS versus ARi double therapies (HR 0.76; 95% CI 0.59–0.97) [21]. However, given the limitations of indirect comparisons, these analyses should be interpreted with caution.

In conclusion, darolutamide plus ADT and docetaxel was more effective in extending OS than placebo plus ADT and docetaxel in the treatment of mHSPC and was associated with a manageable tolerability profile. Darolutamide expands the availability of treatments for mHSPC, and although further study is needed, triple therapy with darolutamide may be useful for patients with high-volume disease.

Data selection darolutamide: 94 records identified

Duplicates removed

0

Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial)

54

Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials)

15

Cited efficacy/tolerability articles

4

Cited articles not efficacy/tolerability

21

Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were Darolutamide, NUBEQA, BAY 1841788, ODM 201, metastatic HSPC, ARASENS. Records were limited to those in English language. Searches last updated 10 Jul 2023