Data from 68 Japanese patients (SPARTAN: n = 34, TITAN: n = 28, PCR1008: n = 6) were analysed; all patients had received apalutamide 240 mg QD orally.
Baseline Characteristics
Since the disease status at baseline was different in SPARTAN, TITAN, and PCR1008 studies, some of the baseline characteristics were not comparable between the three groups, with the median time from initial diagnosis, PSA levels, treatment durations, and ALP levels varying between the 3 patient populations (Table 1).
Table 1
Baseline Characteristics (Safety Set)
Categories
|
SPARTAN
|
TITAN
|
PCR1008
|
Total
|
Number of patients in safety analysis set, n
|
34
|
28
|
6
|
68
|
Median age (years)
|
79.00
|
73.00
|
78.00
|
77.00
|
Median weight (kg)
|
61.90
|
63.55
|
57.30
|
61.80
|
Median height (cm)*
|
163.50
|
165.20
|
163.55
|
164.00
|
ECOG PS*, n (%)
|
|
|
|
|
0
|
30 (88.24)
|
25 (89.29)
|
5 (83.33)
|
60 (88.24)
|
1
|
4 (11.76)
|
3 (10.71)
|
1 (16.67)
|
8 (11.76)
|
Median time from initial diagnosis to first dose (month)
|
87.10
|
2.19
|
68.89
|
46.42
|
GS at initial diagnosis, n (%)
|
|
|
|
|
≤ 7
|
9 (26.47)
|
1 (3.57)
|
2 (33.33)
|
12 (17.65)
|
≥ 8
|
25 (73.53)
|
27 (96.43)
|
4 (66.67)
|
56 (82.35)
|
Median PSA [ng/mL] at baseline
|
4.35
|
11.51
|
54.42
|
5.73
|
Median Hemoglobin [ng/mL]
|
12.95
|
13.45
|
11.95
|
13.10
|
Median LDH (U/L)
|
-
|
198.00
|
192.00
|
197.50
|
Median ALP (U/L)
|
73.50
|
104.50
|
204.50
|
87.00
|
Disease status, n
|
|
|
|
|
nmCRPC
|
55
|
-
|
-
|
55
|
mCSPC
|
-
|
51
|
-
|
51
|
mCRPC
|
-
|
-
|
6
|
6
|
Tumor volume**, n (%)
|
|
|
|
|
High
|
-
|
18 (64.29)
|
-
|
18 (64.29)
|
Low
|
-
|
10 (35.71)
|
-
|
10 (35.71)
|
Previous treatment, n (%)
|
|
|
|
|
Local treatment
|
21 (61.76)
|
1 (3.57)
|
2 (33.33)
|
24 (35.29)
|
RP
|
5 (14.71)
|
1 (3.57)
|
1 (16.67)
|
7 (10.29)
|
RT
|
19 (55.88)
|
1 (3.57)
|
1 (16.67)
|
21 (30.88)
|
Hormonal treatment
|
34 (100.00)
|
28 (100.00)
|
6 (100.00)
|
68 (100.00)
|
LHRHa
|
34 (100.00)
|
28 (100.00)
|
5 (83.33)
|
67 (98.53)
|
Orchiectomy
|
1 (2.94)
|
2 (7.14)
|
1 (16.67)
|
4 (5.88)
|
1st generation AA
|
33 (97.06)
|
15 (53.57)
|
6 (100.00)
|
54 (79.41)
|
Other
|
2 (5.88)
|
0 (0.00)
|
0 (0.00)
|
2 (2.94)
|
Chemotherapy
|
0 (0.00)
|
0 (0.00)
|
0 (0.00)
|
0 (0.00)
|
Other
|
3 (8.82)
|
0 (0.00)
|
2 (33.33)
|
5 (7.35)
|
Incidence Rate, Types of Rash, Severity
In the global SPARTAN and TITAN studies, the overall incidence of skin rash in the apalutamide group was 191/803 (23.8%) and 142/524 (27.1%), respectively, with the combined incidence rates of the most commonly reported rash in the 2 studies, i.e., rash, generalized rash, and maculo-papular rash, being 167/1327 (12.6%), 53/1327 (4.0%), and 60/1327 (4.5%), respectively (Supplementary Table 1). In the present integrated analysis of Japanese patients from SPARTAN and TITAN, and PCR1008, skin rash was observed in 35/68 (51.5%) of the patients, and the incidence rates of rash (13/68 [19.1%]), generalized rash (11/68 [16.2%]), and maculo-papular rash (11/68 [16.2%]) (Table 2) were also higher than that observed in the global studies. Also, the incidence rate of the less commonly observed rash, erythema multiforme and stomatitis, were higher in Japanese patients (3/68 [4.4%], each) compared to their combined incidence rates in the global SPARTAN and TITAN studies (6/1327 [0.45%] and 10/1327 [0.75%], respectively) (Supplementary Table 1).
Table 2
Types of Skin Rash in Apalutamide-treated Patients
Analysis Set (N = 68)
|
Total
n (%)
|
Grade 1
n (%)
|
Grade 2
n (%)
|
Grade 3
n (%)
|
Rash
|
35 (51.47)
|
9 (13.23)
|
16 (23.52)
|
10 (14.70)
|
Rash
|
13 (19.11)
|
8 (11.76)
|
4 (5.88)
|
1 (1.47)
|
Rash maculo-papular
|
11 (16.17)
|
2 (2.94)
|
6 (8.2)
|
3 (4.41)
|
Rash generalised
|
11 (16.17)
|
1 (1.47)
|
7 (10.29)
|
3 (4.41)
|
Erythema multiforme
|
3 (4.41)
|
0
|
1 (1.47)
|
2 (2.94)
|
Stomatitis
|
3 (4.41)
|
1 (1.47)
|
2 (2.94)
|
0
|
Urticaria
|
2 (2.94)
|
2 (2.94)
|
0
|
0
|
Blister
|
1 (1.47)
|
1 (1.47)
|
0
|
0
|
Drug eruption
|
1 (1.47)
|
0
|
0
|
1 (1.47)
|
Rash macular
|
1 (1.47)
|
0
|
0
|
1 (1.47)
|
Skin erosion
|
1 (1.47)
|
1 (1.47)
|
0
|
0
|
Skin exfoliation
|
1 (1.47)
|
1 (1.47)
|
0
|
0
|
In the global SPARTAN and TITAN studies, the incidence of Grade 1 skin rash was 69/803 (8.6%) and 57/524 (10.9%), respectively, in the apalutamide group, while the corresponding values for Grade 2 events were 80/803 (10.0%) and 52/524 (9.9%), respectively (Supplementary Table 1). In the Japanese patients analysed for this study, the incidence of Grade 1 rash was similar between the groups (SPARTAN: 4/34 [11.8%], TITAN: 4/28 [14.3%], PCR1008: 1/6 [16.7%]), with overall incidence being 9/68 (13.2%); Grade 2 rash were more frequently observed in the SPARTAN study (10/34 [29.4%]) compared to the TITAN (5/28 [17.9%]) and PCR1008 (1/6 [16.7%]) studies; while Grade 3 rash was observed only in the SPARTAN (5/34 [14.7%]) and TITAN (5/28 [17.9%]) studies. Overall, Grade 3 skin rash occurred in 10/68 (14.7%) patients in the current integrated analysis, compared to 42/803 (5.2%) and 33/524 (6.3%) patients in the SPARTAN and TITAN global studies, respectively. (Supplementary Table 1) There were no Grade 4 or 5 rashes due to the grading criteria used for reporting the types of rash observed.
Management of Rash
All Japanese patients with skin rash (35/68 [51.1%]) received supportive medications; oral antihistamine was the most common (25/35 [71.4%]), followed by systemic and topical corticosteroids (18/35 [51.4%] and 15/35 [42.9%], respectively) (Table 3). In comparison, in the global SPARTAN and TITAN studies, antihistamines were required in 35% and 38% patients, systemic corticosteroids in 17% and 20% patients, while topical corticosteroids were administered in 34% and 43% patients, respectively (Supplementary Table 2).
Table 3
Analysis Set (N = 68)
|
SPARTAN
|
TITAN
|
PCR1008
|
Total
|
Number of patients in safety analysis set, n
|
34
|
28
|
6
|
68
|
Rash, n (%)
|
19 (55.88)
|
14 (50.00)
|
2 (33.33)
|
35 (51.47)
|
Patients who received supportive care for rash, n (%)
|
|
|
|
|
Oral antihistamine
|
15 (78.95)
|
10 (71.43)
|
0 (0.00)
|
25 (71.43)
|
Systemic corticosteroid
|
4 (21.05)
|
14 (100.00)
|
0 (0.00)
|
18 (51.43)
|
Topical corticosteroid
|
15 (78.95)
|
0 (0.00)
|
0 (0.00)
|
15 (42.86)
|
Drug interruption
|
11 (57.89)
|
6 (42.86)
|
1 (50.00)
|
18 (51.43)
|
Dose reduction
|
4 (21.05)
|
3 (21.43)
|
0 (0.00)
|
7 (20.00)
|
Drug discontinuation
|
3 (15.79)
|
2 (14.29)
|
0 (0.00)
|
5 (14.29)
|
Other
|
0 (0.00)
|
0 (0.00)
|
1 (50.00)
|
1 (2.86)
|
Drug interruptions and dose reductions were required in 18/35 (51.4%) and 7/35 (20.0%) patients, respectively, with treatment discontinuation required in 5/35 (14.3%) patients. Among patients receiving apalutamide who developed skin rash in the global SPARTAN study, treatment discontinuations, dose reductions, and dose interruptions were reported in 19/191 (9.9%), 22/191 (11.5%), and 55/191 (28.8%) patients, respectively, while the corresponding values in the global population from the TITAN study were 12/142 (8.5%), 28/142 (19.7%), and 44/142 (31.0%) (Supplementary Table 2).
Time-to-event analyses
In the integrated analysis, the median time to onset of first incidence of rash of any grade in Japanese patients was 66 days, with time to incidence of first Grade 3 rash being 45 days and 9/10 (90.0%) Grade 3 events being reported in the first 4 months. The median time for first incidence of Grade 3 rash was 52 days and 38 days in the Japanese patients from SPARTAN and TITAN, respectively. In comparison, in the global population from the SPARTAN and TITAN studies, the median time to first incidence of skin rash were 82 days and 80.5 days, respectively (Supplementary Table 2). The median time for remission of first incidence of any grade in Japanese patients was 1.0 month (Fig. 1). In the global population of the SPARTAN study, skin rash of any grade resolved for 81% of the patients within ~ 2 months, while the median time to resolution of skin rash of any grade in the TITAN study was 100 days (Supplementary Table 2). The time to remission of Grade 3 rash was 35 days and 17 days in the Japanese patients from SPARTAN and TITAN, respectively, with 1.0 month required for remission in the integrated analysis (Fig. 2).
Clinical Risk Factors
A number of clinical risk factors that could potentially affect the incidence of rash were assessed, including Eastern Cooperative Oncology Group Performance Status (ECOG PS), time from initial diagnosis to first dose, Gleason score, and previous treatments (Table 4). However, none of the factors were found to be significantly linked to the incidence of skin rash.
Table 4
Odds Ratio (All Grade), Target Population: Safety
Categories
|
Number of Patients
|
Rash, n (%)
|
95% CI
|
Odds Ratio
|
Yes
|
No
|
Number of patients in safety analysis set, n
|
68
|
35 (51.47)
|
33 (48.5)
|
|
|
Age class 1, year
|
< 65
|
5
|
3 (60.00)
|
2 (40.00)
|
|
|
≥ 65
|
63
|
32 (50.79)
|
31 (49.20)
|
0.11–4.40
|
0.69
|
Age class 2, year
|
< 75
|
28
|
13 (46.43)
|
15 (53.57)
|
|
|
≥ 75
|
40
|
22 (55.00)
|
18 (45.00)
|
0.53–3.72
|
1.41
|
Baseline weight
|
< Median
|
34
|
16 (47.06)
|
18 (52.94)
|
|
|
≥ Median
|
34
|
19 (55.88)
|
15 (44.12)
|
0.55–3.70
|
1.43
|
Baseline height
|
< Median
|
34
|
15 (44.12)
|
19 (55.88)
|
|
|
≥ Median
|
34
|
20 (58.82)
|
14 (41.18)
|
0.69–4.73
|
1.81
|
Body mass index (kg/m2)
|
< 25
|
48
|
22 (45.83)
|
26 (54.17)
|
|
|
≥ 25
|
20
|
13 (65.00)
|
7 (35.00)
|
0.75–6.46
|
2.19
|
ECOG PS
|
0
|
60
|
30 (50.00)
|
30 (50.00)
|
|
|
1
|
8
|
5 (62.50)
|
3 (37.50)
|
0.37–7.61
|
1.67
|
Time from initial diagnosis to first dose
|
< Median
|
34
|
14 (41.18)
|
20 (58.82)
|
|
|
≥ Median
|
34
|
21 (61.76)
|
13 (38.24)
|
0.87–6.10
|
2.31
|
GS at initial diagnosis
|
≤ 7
|
12
|
9 (75.00)
|
3 (25.00)
|
|
|
≥ 8
|
56
|
26 (46.43)
|
30 (53.57)
|
0.07–1.18
|
0.29
|
Unknown
|
0
|
0
|
0
|
-
|
-
|
Baseline PSA
|
< Median
|
34
|
21 (61.76)
|
13 (38.24)
|
|
|
≥ Median
|
34
|
14 (41.18)
|
20 (58.82)
|
0.16–1.15
|
0.43
|
Baseline Hemoglobin
|
High
|
68
|
35 (51.47)
|
33 (48.53)
|
|
|
Normal or Low
|
0
|
0
|
0
|
-
|
-
|
Baseline LDH
|
High
|
7
|
2 (28.57)
|
5 (71.43)
|
|
|
Normal or Low
|
27
|
14 (51.85)
|
13 (48.15)
|
0.44–16.37
|
2.69
|
Baseline ALP
|
High
|
13
|
4 (30.77)
|
9 (69.23)
|
|
|
Normal or Low
|
55
|
31 (56.36)
|
24 (43.64)
|
0.80–10.59
|
2.91
|
Previous local treatment
|
No
|
44
|
21 (47.73)
|
23 (52.27)
|
|
|
Yes
|
24
|
14 (58.33)
|
10 (41.67)
|
0.56–4.19
|
1.53
|
Previous 1st generation AA
|
No
|
14
|
9 (64.29)
|
5 (35.71)
|
|
|
Yes
|
54
|
26 (48.15)
|
28 (51.85)
|
0.15–1.74
|
0.52
|
Previous chemotherapy
|
No
|
68
|
35 (51.47)
|
33 (48.53)
|
|
|
Yes
|
0
|
0
|
0
|
-
|
-
|
AA, antiandrogen; ALP, alkaline phosphatase; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GS, Gleason score; LDH, lactate dehydrogenase; PSA, prostate-specific antigen |
Pharmacokinetic Analysis
AUC0 − 24ss of apalutamide were numerically slightly higher in patients with skin rash than those without; however, this did not significantly impact the grade of skin rash (Fig. 3a). No correlation was apparent with AUC0 − 24ss of N-desmethyl apalutamide (Fig. 3b).