The baseline characteristics of 170 mCRPC patients are summarized in Table 1. In total, IDC-P was confirmed in 91/170 (53.5%) patients. Among them, 122 and 48 patients received ABI and DOC, 36/91 (39.6%) and 55/91 (60.4%) had IDC-P pattern 1 and pattern 2, respectively. Patients harboring IDC-P pattern 2 were associated with younger age. Other baseline factors were well balanced among different groups. The median follow-up time was 34.4-mo for the whole cohort. 104/170 (61.2%) patients died during the follow-up. As shown in table S2, 40/122 (32.8%) of our patients in ABI group and 12/48 (25.0%) in DOC group received one or more sequencing treatments after first-line therapy, including abiraterone (n=11), docetaxel (n=30), enzalutamide (n=7), olaparib (n=4), proxalutamide (n=2), pembrolizumab (n=1), pazopanib (n=1) and everolimus (n=1).
The clinical outcomes of mCRPC in the whole cohort
For the total 170 patients, the median PSA-PFS , rPFS and OS were 7.9-mo, 13.7-mo and 24.8-mo, respectively. The presence of IDC-P was associated with unfavorable clinical outcomes compared to those without IDC-P (PSA response rate: 42/91 [46.2%] vs. 50/79 [63.3%], P=0.025, mPSA-PFS: 6.6-mo vs. 10.6-mo, P=0.001; mrPFS: 11.2-mo vs 18.0-mo, P<0.001; mOS: 21.9-mo vs. 30.0-mo, P=0.076). Among patients treated with ABI (n=122), PSA response was achieved in 71/122 (58.2%) cases, the median PSA-PFS, rPFS and OS was 9.1-mo, 14.8-mo and 27.4-mo respectively. In DOC treatment cohort (n=48), PSA response occurred in 21/48 (43.8%) men, the median PSA-PFS, rPFS and OS were 5.6-mo, 8.9-mo and 21.5-mo, respectively (Table 2).
The prognostic value of IDC-P architectural patterns in patients treated with abiraterone
Among patients treated with ABI, PSA response was similar between cases with and without IDC-P (52.4%[33/63] vs. 64.4%[38/59], P=0.245) (Figure S1A). However, IDC-P was associated with shorter median PSA-PFS (7.9-mo vs. 11.9-mo, P =0.012), rPFS (11.9-mo vs 18.9-mo, P =0.003), and OS (25.4-mo vs. 31.1-mo, P=0.031) (Figure S1 B-D). Multivariate Cox regression further confirmed that IDC-P, together with GS and ALP level, was one of the independent prognosticators predicting worse clinical outcomes in the first-line ABI treatment of mCRPC. (Table 3).
The therapeutic efficacy of ABI treatment in patients with different IDC-P sub-patterns was further explored. Clinical outcomes of patients with IDC-P pattern 1 and those without IDC-P were similar (Figure 2). On the contrary, cases with IDC-P pattern 2 were associated with much poorer prognosis than patients with IDC-P pattern 1 (mPSA-PFS: 6.1 vs.11.1-mo, P=0.001; mrPFS: 9.6 vs. 19.4-mo, P<0.001; mOS: 23.1 vs. 27.0-mo, P=0.596) or those without IDC-P (mPSA-PFS: 6.1 vs. 11.9-mo, P<0.001; mrPFS: 9.6 vs.18.9-mo, P<0.001; mOS: 23.1 vs. 31.1-mo, P=0.037) (Figure 2 B-D). Multivariate COX regression after adjusting other prognosticators further strengthened these findings (Table 3). In addition, the proportion of IDC-P was not found to be related to the efficacy of ABI.
The prognostic value of different IDC-P architectural patterns in patients treated with docetaxel
Among patients treated with DOC, IDC-P was also a predictor of poor prognosis (Figure S2 and Table S1). IDC-P-carriers had shorter median PSA-PFS (5.1-mo vs. 6.2-mo, P=0.038), rPFS (15.1-mo vs 6.8-mo, P=0.011) against the non-carriers (Figure S2 B-C). Yet only numerically lower PSA response rate and shorter OS time were found in patients with IDC-P than those without IDC-P (PSA response: 9/28 [32.1%] vs. 12/20 [60.0%], P=0.055; mOS: 17.8-mo vs. 22.3-mo, P=0.569) (Figure S2 A, D). Multivariate Cox regression further confirmed that the presence of IDC-P was an independent factor predicting worse PSA-PFS and rPFS in DOC treatment (Table S1). Similarly, the proportion of IDC-P was not found to be related to the efficacy of DOC.
Subgroup analysis revealed that patients with IDC-P pattern 1 and without IDC-P shared similar clinical outcomes in DOC treatment, whereas cases with IDC-P pattern 2 had much poorer PSA-PFS and rPFS (Figure 3). Multivariate COX regression after adjusting other prognosticators also confirmed this finding (Table S1).
Comparison of efficacy between ABI and DOC for IDC-P (-), IDC-P pattern 1 and IDC-P pattern 2 patients
For mCRPC patients without IDC-P (n=79), the therapeutic efficacy of ABI and DOC were comparable. No significant difference on PSA response rate (38/59 [64.4%] vs. 12/20 [60.0%], P=0.724) (Figure S3 A), median PSA-PFS (11.9-mo vs. 6.23-mo, P=0.158), rPFS (18.9-mo vs. 15.1-mo, P=0.213) and OS (31.1-mo vs. 22.33-mo, P=0.188) was found between ABI and DOC treatment (Figure 4 and Figure S4 A-C).
Notably, among patients with IDC-P pattern 1 (n=36), ABI brought significantly longer PSA-PFS (11.1-mo vs. 6.6-mo, P=0.022) and rPFS (19.4-mo vs. 12.6-mo, P=0.027) compared to DOC. Despite lacking statistical significance, the OS of patients with IDC-P pattern 1 receiving ABI treatment was numerically longer than those treated with DOC (27.0-mo vs. 14.4-mo, P=0.535) (Figure 4 and Figure S4 D-F). The PSA response rate was similar between ABI and DOC treatment (14/23 [60.9%] vs. 5/13 [38.5%], P=0.299) (Figure S3B) in IDC-P pattern 1 carriers. Additionally, COX regression suggested ABI was superior to DOC in prolonging PSA-PFS (HR=2.24, 95% CI: 1.01-4.96, P=0.047) and rPFS (HR=3.37, 95% CI: 1.49-7.63, P=0.004) among patients with IDC-P pattern 1 (Table 4).
Based on the current analysis, ABI still showed relatively better clinical efficacy than DOC in patients harboring IDC-P pattern 2. Higher PSA response, prolonged PSA-PFS, rPFS and OS was found in patients treated with ABI versus DOC (PSA response: 47.5% vs. 26.7%, P=0.163; mPSA-PFS: 6.0 vs. 3.1-mo, P=0.003; mrPFS: 9.6 vs. 5.5-mo, P=0.007; mOS: 23.1 vs. 17.8-mo, P=0.890) (Figure S3B, Figure 4 and Figure S4 G-I). However, it cannot be neglected that even though ABI showed superior efficacy than DOC in cases with IDC-P pattern 2, it still only provides very limited benefits for this group of patients. Honestly speaking, patients with IDC-P pattern 2 was actually associated with rapid disease progression and poorer response to the current standard of care for mCPRC.