In total, 1207 patients in SPARTAN and 1052 patients in TITAN were enrolled globally, of which 55 and 51 patients were Japanese, respectively. This integrated analysis included data from total 68 Japanese patients (SPARTAN: n=34, TITAN: n=28, PCR1008: n=6) who had received apalutamide 240 mg QD orally (Figure 1).
Overall, the median age of patients was 77 years. 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. Median time from initial diagnosis to first dose was shortest in TITAN (2.19 months), followed by PCR1008 (68.89 months) and SPARTAN (87.10 months); with median PSA level [ng/mL] at baseline of 11.51, 54.42 and 4.35, respectively. All patients had received prior hormonal therapy (Table 1).
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).
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 analyzed 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).
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, dose interruptions, does reductions, and treatment discontinuations were reported in 55/191 (28.8%), 22/191 (11.5%), and 19/191 (9.9%), patients, respectively, while the corresponding values in the global population from the TITAN study were 44/142 (31.0%), 28/142 (19.7%), and 12/142 (8.5%) (Supplementary Table 2).
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 (Interquartile range [IQR]: 0.36-1.81) (Figure 2). In the global population of the SPARTAN study, skin rash of any grade resolved for 81% of the patients within 59.5 days, 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 (IQR: 0.30-2.43) required for remission in the integrated analysis (Figure 3). Some patients experienced skin rash more than once during apalutamide treatment. Even if patients resolved first incidence of rash, there was the potential for worsening in the second incidence of rash. Therefore, we assessed these two types of KM curves. KM figures for time-to-rash (All grade) (Supplementary Figure 1), time-to-rash (≥Grade3) (Supplementary Figure 2), time-to-remission of first incidence (≥Grade3) (Supplementary Figure 3), and time-to-remission of maximum grade (≥Grade3) (Supplementary Figure 4) are included in the supplementary files.
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.
AUC0-24, ss 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 (Figure 4a). No correlation was apparent with AUC0-24, ss of N-desmethyl apalutamide (Figure 4b).