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On March 24, 2022, the New England Journal of Medicine (NEJM) published the results of
the ARASENS trial for darolutamide in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
The results of this trial suggest that androgen deprivation therapy, docetaxel, and daroxamide improve overall survival, and improvements were observed for key secondary endpoints in patients with mHSPC, with no increase
in adverse events.
The results of this study will have a significant impact on the treatment strategy of mHSPC patients and have attracted the attention
of urologists.
Here, we briefly introduce the results of the study for the benefit of our readers
.
likelihood of clinically meaningful drug interactions 。 Studies conducted in prostate cancer patients, including the Phase 3 ARAMIS [Androgen Receptor Antagonizing Agent for Metastasis-free Survival] trial, in patients with non-metastatic castration-resistant prostate cancer, have shown that darolutamide has a strong antitumor efficacy
。 In the ARAMIS trial, patients in the darolutamide + ADT group had a median metastasis-free survival almost 2 years longer and a 31% lower risk of death compared with those in the placebo + ADT group, with similar rates of adverse events in both groups
.
However, it is unclear
whether combination therapy with darolutamide, ADT, and docetaxel improves survival in patients with mHSPC.
In this international, randomized, double-blind, placebo-controlled phase 3 trial, investigators randomized patients with mHSPC in a 1:1 ratio to receive either darolutamide (600 mg twice daily [2 300 mg pills]) or matched placebo, both in combination with ADT and docetaxel
.
The primary endpoint is overall survival
.
Secondary endpoints included time to castration-resistant prostate cancer, time to pain progression, survival to asymptomatic skeletal event, time to first symptomatic skeletal event, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related somatic symptoms, time to initiation of opioid therapy ≥ 7 days, and safety
.
Between November 2016 and June 2018, a total of 1306 patients were randomized at 286 sites in 23 countries
.
The darolutamide and placebo groups included 651 and 655 patients, respectively, who were treated with darostatamide and placebo
, respectively.
Of these patients, 1305 patients (651 in the darolutamide group and 654 in the placebo group) were included in the full analysis set, and 1302 patients (652 in the darolutamide group and 650 in the placebo group) were included in the safety analysis set
.
Balance of demographic and baseline characteristics of both groups (Table 1).
The median age of patients in both groups was 67 years old, and most patients (71.
1%) had a performance status score of 0 in the Eastern Oncology Collaborative Group (ECOG), and 78.
2% had a Gleason score of ≥ 8 (the score range was 6~10 points, with a higher score indicating a higher aggressiveness of prostate cancer).
All patients had metastatic disease at baseline; 79.
5% had bone metastases (metastatic stage M1b) and 17.
5% had visceral metastases (metastatic stage M1c).
At initial diagnosis, most patients (86.
1%) had metastatic disease
.
At the data cut-off date for the primary analysis (25 October 2021), the median duration of treatment was longer in the darrotamide group compared with the placebo group (41.
0 months vs.
16.
7 months), with a higher percentage of patients still receiving their assigned trial therapy (45.
9% [299/651 patients] vs.
19.
1% [125/654 patients]).
Five of the 652 patients (87.
6%) in the darolutamide group and 556 (85.
5%) of the 650 patients in the placebo group completed six cycles of docetaxel
.
The median follow-up for overall survival in the darolutamide and placebo groups was 43.
7 and 42.
4 months
, respectively.
of overall survival was performed after the death of 533 patients (229 patients in the darolutamide group and 304 patients in the placebo group).
Compared with the placebo group, the risk of death was reduced by 32.
5% in the darolutamide group (hazard ratio, 0.
68; 95% confidence interval [CI], 0.
57~0.
80; P<0.
001) (Figure 1).
Although a large proportion (374/495 patients [75.
6%]) in the placebo group received subsequent life-prolonging systemic therapy (mainly different androgen receptor pathway inhibitors), significant improvement
in overall survival was observed in the dalottamide group.
In the darolutamide group and placebo group, the overall survival rates at 4 years were 62.
7% (95% CI, 58.
7~66.
7) and 50.
4% (95% CI, 46.
3~54.
6),
respectively.
In most subgroups, darolutamide was more effective in improving overall survival
.
Figure 1 Overall lifetime (full analysis set).
In the darolutamide group, the time to the development of castration-resistant prostate cancer was significantly longer (risk ratio, 0.
36; 95% CI, 0.
30~0.
42; P<0.
001).
。 In the darolutamide group, the time to pain progression (risk ratio, 0.
79; 95% CI, 0.
66~0.
95; P=0.
01), survival to asymptomatic skeletal events (hazard ratio, 0.
61; 95% CI, 0.
52~0.
72; P<0.
001) and time to first symptomatic skeletal event (hazard ratio, 0.
71; 95% CI, 0.
54~0.
94; P=0.
02) were also significantly longer
。 In the darolutamide group, the time from the start of subsequent systemic antineoplastic therapy was significantly longer (risk ratio, 0.
39; 95% CI, 0.
33~0.
46; P<0.
001).
The incidence of the most common (≥10% of patients) adverse events (many of which are known toxic effects associated with docetaxel treatment) was highest in both groups during treatment with docetaxel and daroxamine or placebo, followed by a gradual reduction
in these adverse events.
Grade 3 or 4 adverse events occurred in 66.
1% of patients in the darolutamide group and 63.
5% in the placebo group; Neutropenia was the most common grade 3 or 4 event (incidence 33.
7% and 34.
2%, respectively).
occurred in 44.
8% of patients in the darolutamide group and 42.
3% in the placebo group.
The incidence of death due to adverse events was lower and similar in both groups (27 of 652 patients in the darutamide group [4.
1%] and 26 of 650 patients in the placebo group [4.
0%]).
Fewer patients discontinued darolutamide or placebo due to adverse events (13.
5% of patients in the darolutamide group and 10.
6% of patients in the placebo group).
The most commonly reported adverse events included alopecia (40.
5% of patients in the darolutamide group and 40.
6% of patients in the placebo group), neutropenia (39.
3% and 38.
8%, respectively), fatigue (33.
1% and 32.
9%), and anemia (27.
8% and 25.
1%)
.
Certain adverse events are of particular concern for patients receiving androgen receptor pathway inhibitors
.
These events include fatigue, falls, fractures, mental impairment, rash, hypertension, and cardiovascular events
.
In this trial, the incidence of these events was similar (difference of no more than 2 percentage points
) in both groups, except for skin rash (16.
6% of patients in the darolutamide group and 13.
5% of patients in the placebo group) and hypertension (13.
7% and 9.
2%, respectively).
Among the most commonly reported adverse events of special concern, vasodilation and flushing (20.
4% of patients in the darolutamide group and 21.
7% of patients in the placebo group) and diabetes mellitus and hyperglycemia (15.
2% and 14.
3%) were also similar in both groups
.
In summary, this trial supports the use of a combination of darolutamide + ADT + docetaxel in patients with mHSPC
.
In patients with mHSPC, the combination of darolotamide + ADT + docetaxel was significantly longer in overall survival than placebo + ADT + docetaxel, and the addition of darolotamide improved key secondary endpoints
.
Adverse event rates were similar
in both groups.
the ARASENS trial for darolutamide in patients with metastatic hormone-sensitive prostate cancer (mHSPC).
The results of this trial suggest that androgen deprivation therapy, docetaxel, and daroxamide improve overall survival, and improvements were observed for key secondary endpoints in patients with mHSPC, with no increase
in adverse events.
The results of this study will have a significant impact on the treatment strategy of mHSPC patients and have attracted the attention
of urologists.
Here, we briefly introduce the results of the study for the benefit of our readers
.
Metastatic prostate cancer is a fatal disease, and the current standard of care for metastatic hormone-sensitive prostate cancer (mHSPC) is androgen deprivation therapy (ADT) plus docetaxel or an androgen receptor inhibitor
.
Two previous phase 3 randomized trials have shown a longer overall survival with ADT plus docetaxel than ADT alone, with greater clinical benefit from ADT in combination with an androgen receptor pathway inhibitor (abiraterone, enzalutamide, or apatamide
).
likelihood of clinically meaningful drug interactions 。 Studies conducted in prostate cancer patients, including the Phase 3 ARAMIS [Androgen Receptor Antagonizing Agent for Metastasis-free Survival] trial, in patients with non-metastatic castration-resistant prostate cancer, have shown that darolutamide has a strong antitumor efficacy
。 In the ARAMIS trial, patients in the darolutamide + ADT group had a median metastasis-free survival almost 2 years longer and a 31% lower risk of death compared with those in the placebo + ADT group, with similar rates of adverse events in both groups
.
However, it is unclear
whether combination therapy with darolutamide, ADT, and docetaxel improves survival in patients with mHSPC.
In this international, randomized, double-blind, placebo-controlled phase 3 trial, investigators randomized patients with mHSPC in a 1:1 ratio to receive either darolutamide (600 mg twice daily [2 300 mg pills]) or matched placebo, both in combination with ADT and docetaxel
.
The primary endpoint is overall survival
.
Secondary endpoints included time to castration-resistant prostate cancer, time to pain progression, survival to asymptomatic skeletal event, time to first symptomatic skeletal event, time to initiation of subsequent systemic antineoplastic therapy, time to worsening of disease-related somatic symptoms, time to initiation of opioid therapy ≥ 7 days, and safety
.
Between November 2016 and June 2018, a total of 1306 patients were randomized at 286 sites in 23 countries
.
The darolutamide and placebo groups included 651 and 655 patients, respectively, who were treated with darostatamide and placebo
, respectively.
Of these patients, 1305 patients (651 in the darolutamide group and 654 in the placebo group) were included in the full analysis set, and 1302 patients (652 in the darolutamide group and 650 in the placebo group) were included in the safety analysis set
.
Balance of demographic and baseline characteristics of both groups (Table 1).
The median age of patients in both groups was 67 years old, and most patients (71.
1%) had a performance status score of 0 in the Eastern Oncology Collaborative Group (ECOG), and 78.
2% had a Gleason score of ≥ 8 (the score range was 6~10 points, with a higher score indicating a higher aggressiveness of prostate cancer).
All patients had metastatic disease at baseline; 79.
5% had bone metastases (metastatic stage M1b) and 17.
5% had visceral metastases (metastatic stage M1c).
At initial diagnosis, most patients (86.
1%) had metastatic disease
.
Table 1 Baseline demographic and clinical features
of the patient.
*** The percentage total may not be 100
due to rounding.
ADT stands for androgen deprivation therapy, ALP for alkaline phosphatase, PSA for prostate-specific antigen, and ULN for upper limit
of normal.
† One patient randomized to placebo but treated with darolutamide was included in the placebo group in the full analysis set
.
‡ The Eastern US Cancer Group (ECOG) performance status score ranges from 0~5 points, and a higher score indicates more severe disability
.
Ethnicity is reported
by researchers.
The "rest of the world" mainly includes European countries, Australia, Brazil, Israel and Mexico
.
‖ The Gleason score of cancer histological pattern ranges from 6~10 points, and a higher score indicates a higher
aggressiveness of prostate cancer.
** These values are evaluated
centrally.
Samples
were taken while the patient received ADT.
At the data cut-off date for the primary analysis (25 October 2021), the median duration of treatment was longer in the darrotamide group compared with the placebo group (41.
0 months vs.
16.
7 months), with a higher percentage of patients still receiving their assigned trial therapy (45.
9% [299/651 patients] vs.
19.
1% [125/654 patients]).
Five of the 652 patients (87.
6%) in the darolutamide group and 556 (85.
5%) of the 650 patients in the placebo group completed six cycles of docetaxel
.
The median follow-up for overall survival in the darolutamide and placebo groups was 43.
7 and 42.
4 months
, respectively.
Primary endpoint
The main analysisof overall survival was performed after the death of 533 patients (229 patients in the darolutamide group and 304 patients in the placebo group).
Compared with the placebo group, the risk of death was reduced by 32.
5% in the darolutamide group (hazard ratio, 0.
68; 95% confidence interval [CI], 0.
57~0.
80; P<0.
001) (Figure 1).
Although a large proportion (374/495 patients [75.
6%]) in the placebo group received subsequent life-prolonging systemic therapy (mainly different androgen receptor pathway inhibitors), significant improvement
in overall survival was observed in the dalottamide group.
In the darolutamide group and placebo group, the overall survival rates at 4 years were 62.
7% (95% CI, 58.
7~66.
7) and 50.
4% (95% CI, 46.
3~54.
6),
respectively.
In most subgroups, darolutamide was more effective in improving overall survival
.
Figure 1 Overall lifetime (full analysis set).
A Kaplan-Meier estimate of overall survival is shown
.
For the analysis of overall survival, the data were censored
on the date of the last known patient survival.
In the full analysis set, one patient randomized to placebo but treated with darolutamide was included in the placebo group
.
CI represents the confidence interval and NE indicates non-estimated
.
Secondary efficacy endpoints
For the first five secondary efficacy endpoints of the cascading test, darolutamide was associated with a significantly larger benefit compared with placebo (Table 2 and Figure 2).In the darolutamide group, the time to the development of castration-resistant prostate cancer was significantly longer (risk ratio, 0.
36; 95% CI, 0.
30~0.
42; P<0.
001).
。 In the darolutamide group, the time to pain progression (risk ratio, 0.
79; 95% CI, 0.
66~0.
95; P=0.
01), survival to asymptomatic skeletal events (hazard ratio, 0.
61; 95% CI, 0.
52~0.
72; P<0.
001) and time to first symptomatic skeletal event (hazard ratio, 0.
71; 95% CI, 0.
54~0.
94; P=0.
02) were also significantly longer
。 In the darolutamide group, the time from the start of subsequent systemic antineoplastic therapy was significantly longer (risk ratio, 0.
39; 95% CI, 0.
33~0.
46; P<0.
001).
Table 2 Secondary efficacy endpoints (full set of analyses).
** NA means not applicable, NR means not reached
.
† 1 patient randomized to placebo but treated with darolutamide was included in the placebo group
.
Panel A shows the time to the onset of castration-resistant prostate cancer, and panel B shows the time
to pain progression.
The Kaplan-Meier method is used to estimate the time to the event; For this endpoint, the data were censored on the date of the
patient's last assessment.
In the full analysis set, one patient randomized to placebo but treated with darolutamide was included in the placebo group
.
security
The incidence of adverse events of any grade, grade 3 to 5, and serious adverse events was similar in both groups (Table 3).The incidence of the most common (≥10% of patients) adverse events (many of which are known toxic effects associated with docetaxel treatment) was highest in both groups during treatment with docetaxel and daroxamine or placebo, followed by a gradual reduction
in these adverse events.
Grade 3 or 4 adverse events occurred in 66.
1% of patients in the darolutamide group and 63.
5% in the placebo group; Neutropenia was the most common grade 3 or 4 event (incidence 33.
7% and 34.
2%, respectively).
Table 3 Adverse events
.
** ALT stands for alanine aminotransferase and AST stands for aspartate aminotransferase
.
† three randomized patients never received the trial treatment as assigned; All three patients were in the placebo group
.
In the safety analysis set, 1 patient who was assigned to placebo but received darolutamide was included in the darolutamide group
.
‡All grade 3 or 4 events
that occurred in at least 2% of patients were listed in the Data column for patients receiving darolutamide, ADT, and docetaxel.
§ Neutropenic types include the preferred terms leukopenia, neutropenia, neutropenia, neutrophil count, and white blood cell count.
occurred in 44.
8% of patients in the darolutamide group and 42.
3% in the placebo group.
The incidence of death due to adverse events was lower and similar in both groups (27 of 652 patients in the darutamide group [4.
1%] and 26 of 650 patients in the placebo group [4.
0%]).
Fewer patients discontinued darolutamide or placebo due to adverse events (13.
5% of patients in the darolutamide group and 10.
6% of patients in the placebo group).
The most commonly reported adverse events included alopecia (40.
5% of patients in the darolutamide group and 40.
6% of patients in the placebo group), neutropenia (39.
3% and 38.
8%, respectively), fatigue (33.
1% and 32.
9%), and anemia (27.
8% and 25.
1%)
.
Certain adverse events are of particular concern for patients receiving androgen receptor pathway inhibitors
.
These events include fatigue, falls, fractures, mental impairment, rash, hypertension, and cardiovascular events
.
In this trial, the incidence of these events was similar (difference of no more than 2 percentage points
) in both groups, except for skin rash (16.
6% of patients in the darolutamide group and 13.
5% of patients in the placebo group) and hypertension (13.
7% and 9.
2%, respectively).
Among the most commonly reported adverse events of special concern, vasodilation and flushing (20.
4% of patients in the darolutamide group and 21.
7% of patients in the placebo group) and diabetes mellitus and hyperglycemia (15.
2% and 14.
3%) were also similar in both groups
.
In summary, this trial supports the use of a combination of darolutamide + ADT + docetaxel in patients with mHSPC
.
In patients with mHSPC, the combination of darolotamide + ADT + docetaxel was significantly longer in overall survival than placebo + ADT + docetaxel, and the addition of darolotamide improved key secondary endpoints
.
Adverse event rates were similar
in both groups.
References
1.
Smith MR, Hussain M, Saad F, et al.
Darolutamide
and survival in metastatic, hormone-sensitive prostate cancer.
N Engl J Med
2022; 386:1132-42.
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The full text of the Chinese translation and the figures contained therein are exclusively licensed
by NEJM Group.
If you want to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
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.
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