A total of 55 mCRPC patients were enrolled and received CBZ; the majority of patients (n = 48) received ≥ 4 cycles of CBZ. Table 1a. shows patient characteristics at baseline; median (range) age was 71 (51–82) years, and median time to CRPC diagnosis was 10 (3–78) months. At the time of diagnosis, 83% (40/48) of patients presented with locally advanced prostate cancer, and 79% (38/48) of patients presented as high-grade prostate cancer (Gleason score of ≥ 8). As local treatment, surgery (radical prostatectomy or robotic laparoscopic prostatectomy) was performed in 13% (6/48) of patients, and radiation therapy (intensity modulated radiation therapy [IMRT] for primary cancer or irradiation to bone metastasis) in 27% (13/48) of patients. Prior hormonal or chemotherapy treatment lines for CRPC before CBZ treatment initiation included: 19% of patients (n = 9) received one line of treatment, 39% (n = 17) received two lines, 26% (n = 13) received three lines, and 19% (n = 9) received ≥ 4 lines of treatment.
Initial treatments for mCRPC included: enzalutamide, abiraterone, Radium-223 chloride, flutamide, ethinylestradiol, estramustine phosphate, and docetaxel. All patients had previously received docetaxel; median (range), 6 (1–39) cycles before CBZ treatment. A total of 17 patients (35%) had received abiraterone, and 30 patients (62%) had received enzalutamide before enrolment, with 10 patients (21%) receiving both enzalutamide and abiraterone (Table 1b).
The median observation period for all 48 CBZ-treated patients was 13.7 (7.3–34.6) months. Median OS for all patients was 13.7 months (95% CI, 12.2–18.9) (Fig. 1). There was no statistically significant difference in the number of treatment lines before CBZ treatment and OS rate (HR, 0.98 [95% CI, 0.41–2.34]; p = 0.19), and no statistically significant difference in time to CRPC and OS (HR, 0.84 [95% CI, 0.37–1.93]; p = 0.85).
At baseline, CTCs were identified in 34 of the 48 blood samples (70.8%), and 8 (16%) of these 34 samples had detectable AR-V7 i.e. AR-V7 positive (Table 2). Seven patients (88%) out of the eight AR-V7 positive patients had previously received enzalutamide or abiraterone, and 2 patients (29%) out of seven AR-V7 positive patients had previously received both enzalutamide and abiraterone.
After a minimum of four cycles of CBZ treatment, the best PSA reduction rate was ≥ 30% in 18 patients (38%) and ≥ 50% in 12 patients (26%) (Fig. 2a). There was no statistically significant difference in PSA best change rate for the CTC negative/AR-V7 positive, CTC positive/AR-V7 negative, and CTC positive/AR-V7 positive groups. PSA-RR (≥ 50%) was observed in 21% (3/ 14) patients in the CTC negative/AR-V7 negative group, 16% (4/25) of patients in the CTC positive/AR-V7 negative group, and 12% (1/8) of patients in the CTC positive/AR-V7 positive group. There were no significant differences between the AR-V7 positive and AR-V7 negative groups (Fig. 2a).
Despite more than three cycles of CBZ, 42% (20/48) of patients did not show a PSA decreasing response to chemotherapy. Overall survival was significantly worse in patients who did not have a PSA decreasing response in the early stages of CBZ treatment (HR, 2.84 [95% CI, 1.22–6.57]; p = 0.00173) (Fig. 2b). Therefore, the PSA decline in the early stages of CBZ treatment could predict better survival with CBZ treatment.
Findings from the CTC analyses showed that median OS was 13.9 months (95% CI, 9.5–22.0) in the AR-V7 positive group, 13.4 months (95% CI, 9.5–20.4) in the CTC positive/AR-V7 negative group, and 16.7 months (95% CI, 7.8–NA) in the CTC negative/AR-V7 negative group (Fig. 3). The presence of AR-V7 in CTCs at baseline was not associated with OS (CTC positive/AR-V7 positive versus CTC positive/AR-V7 negative, HR: 1.02 [95% CI, 0.28–3.71]; p = 0.97; CTC positive/AR-V7 positive versus CTC negative/AR-V7 negative, HR: 0.89 [95% CI 0.34–2.27]; p = 0.80).
During cabazitaxel treatment, BSI change rates were available for 41 patients: 9 patients (19%) achieved a ≥ 30% reduction, and 8 patients (17%) achieved a ≥ 50% reduction after 12 weeks of CBZ treatment (Fig. 4a). From the CTC analysis, there was no statistically significant difference in BSI change rate for the CTC negative, CTC positive/AR-V7 negative, and CTC positive /AR-V7 positive groups. However, OS was significantly worse in patients who did not have a BSI decreasing response after CBZ treatment (HR, 1.75 [95% CI, 0.66–4.67]; p = 0.0194). (Fig. 4b). Therefore, the effect of CBZ treatment on bone metastases objectively evaluated by bone scintigraphy BSI could predict favorable survival during CBZ treatment.
For adverse events of grade 2–3 and above, CBZ administration was continued with appropriate dose reductions. The use of filgrastim prevented severe febrile neutropenia (FN) for most patients and treatment-related death, although FN of G3 or higher developed and the dose of CBZ was reduced in six cases. Although CBZ administration was not discontinued, blood transfusion was required in 4 patients with G3 anemia and 1 patient with G3 thrombocytopenia. Four cases withdrew in less than 3 cycles due to exacerbation of prostate cancer and for 3 patients, CBZ was discontinued before the completion of 4 cycles, due to other disease causes (cerebral hemorrhage, myocardial infarction, other advanced cancers). As a result, a total of seven out of 55 entry patients withdrew in less than 3 cycles of CBZ.