Reports of Bone Scan Index (BSI) calculations as imaging biomarkers to predict survival in patients with metastatic castration-resistant prostate cancer (mCRPC) have been mainly from retrospective studies. To evaluate the effectiveness of enzalutamide (ENZ) in Japanese patients with mCRPC and bone metastases using BSI (bone scintigraphy) and circulating tumor cell (CTC) analysis. Prospective, single-arm study at Juntendo University affiliated hospitals, Japan. Patients were administered 160 mg ENZ daily, with 3 monthly assessments: BSI, prostate specific antigen (PSA), CTC and androgen receptor splicing variant-7 (AR-V7) status. Primary endpoint: BSI-decreasing rate after ENZ treatment. Secondary endpoints: PSA-decreasing rate and progression free survival (PFS). Statistical analyses included the Wilcoxon t-test, Cox proportional hazard regression analysis, and log-rank test. Median observation period: 17.9 months, and median PFS: 13.8 (2.0–43.9) months (n = 90 patients). A decrease in BSI compared to baseline as best BSI change on ENZ treatment was evident in 69% patients at the end of the observation period (29% patients showed a complete response, BSI 0.00). At 3 months 67% patients showed a ≥ 50% PSA reduction, and 70% after ENZ treatment. PSA decline (3 months) significantly associated with a prolonged median PFS: 18.0 (estimated) versus 6.4 months (HR 2.977 [95% CI 1.53–5.78], p = 0.001). Best BSI decline response significantly associated with a prolonged PFS: 18.1(estimated) versus 7.8 months (HR 2.045 [95% CI: 1.07–3.90], p = 0.029). CTC negative status (n = 20) significantly associated with a prolonged PFS: 13.4 [estimated] vs 8.6 months (HR 2.366, 95% CI 0.97–5.71, p = 0.041). CTC positive/AR-V7 positive status significantly associated with a shorter PFS: 5.9 months (HR 8.56, 95% CI 2.40–30.43, p = 0.0087). -reduction (3 months) and BSI-reduction (on ENZ treatment) were significant response biomarkers, and a negative CTC status was a predictive factor for ENZ efficacy in patients with mCRPC.
Androgen receptor splice variant-7 (AR-V7) expression in circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with abiraterone and enzalutamide resistance. We determine whether cabazitaxel (CBZ) is equally effective in AR-V7-positive and -negative CRPC and whether AR-V7-positive patients retain CBZ sensitivity. This is the first prospective, open-label, Asian validation study of CBZ in Japanese patients with mCRPC after docetaxel (n = 48; four CBZ cycles; 2017–2020, Juntendo University Hospitals). Primary endpoint was prostate-specific antigen response rate (PSA-RR); secondary endpoints included overall survival (OS), bone scan index (BSI) PSA-RR (≥ 50% decline from baseline) for CTC−/ARV7−, CTC+ /ARV7−, and CTC +/ARV7+ groups. PSA-RR ≥ − 30% was 38% (18/48) and ≥ − 50% was 26% (12/48). BSI-change rate ≥ − 30% was 19% (9/41) and ≥ − 50% was 17% (8/41). Median OS was 13.7(12.2–18.9) months. PSA decline in early CBZ treatment associated with OS (p = 0.00173). BSI decline associated with OS (p = 0.0194). PSA-RR(≥ 50%) was 43%(6/14) in CTC−/ARV7−, 19%(5/26) in CTC+ ARV7−, and 12%(1/8) in CTC+/ARV7+ ( p > 0.05). AR-V7 in CTCs at baseline not associated with OS. AR-V7 was not associated with CBZ resistance in CTCs. Reductions in BSI and PSA in early stages of CBZ treatment may predict OS.
Background Reports of Bone Scan Index (BSI) calculations as imaging biomarkers to predict survival in patients with metastatic castration-resistant prostate cancer (mCRPC) have been mainly from retrospective studies. To evaluate the effectiveness of enzalutamide (ENZ) in Japanese patients with mCRPC and bone metastases using BSI (bone scintigraphy) and circulating tumor cell (CTC) analysis. Methods Prospective, single-arm study at Juntendo University affiliated hospitals, Japan. Patients were administered 160 mg ENZ daily, with 3-monthly assessments: BSI, prostate specific antigen (PSA), CTC and androgen receptor splicing variant-7 (AR-V7) status. Primary endpoint: BSI-decreasing rate after ENZ treatment. Secondary endpoints: PSA and progression free survival (PFS). Statistical analyses included the Wilcoxon t-test, Cox proportional hazard regression analysis, and log-rank test. Results Median observation period: 17.9 months, and median PFS: 13.8 (2.0-43.9) months (n = 90 patients). At 3 months 67% patients showed a ≥ 50% PSA reduction, and 70% after ENZ treatment. At 3 months 20% patients showed a ≥ 50% BSI reduction (10% complete response [CR]; BSI value 0.00), and 38% patients (29% CR) at study end. PSA decline (3 months) significantly prolonged median PFS: 18.0 (estimated) vs 6.4 months (HR 2.977 [95% CI: 1.53–5.78], p = 0.001). Best BSI decline response significantly prolonged PFS: 18.1(estimated) vs 7.8 months (HR 2.045 [95% CI: 1.07–3.90], p = 0.029). CTC negative status (n = 20) significantly prolonged PFS: 13.4 [estimated] vs 8.6 months (HR 2.366, 95% CI: 0.97–5.71, p = 0.041). CTC positive/AR-V7 positive status significantly reduced PFS: 5.9 months (HR 8.56, 95%CI: 2.40–30.43, p = 0.0087). Conclusions PSA reduction (3 months), BSI reduction (after ENZ), and a negative CTC status were significant predictive factors for ENZ efficacy in patients with mCRPC.
BACKGROUND: Androgen receptor splice variant-7(AR-V7) expression in circulating tumor cells(CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with resistance to abiraterone and enzalutamide. We had objectives to determine whether cabazitaxel(CBZ) was equally effective in AR-V7 positive and negative CRPC, and if AR-V7 positive patients retained CBZ sensitivity.METHODS: This study was first-of-a-kind, Asian validation, prospective, open-label study: CBZ in Japanese mCRPC patients after docetaxel. 48 patients completed 4 CBZ cycles (recruited: 2017–2020, Juntendo University Hospitals). Primary endpoint was prostate-specific antigen response rate(PSA-RR), and secondary endpoints were overall survival(OS), Bone Scan Index[BSI]-change rate of bone metastases by bone scintigraphy, and safety assessments. PSA-RR(≥50% decline from baseline) for: CTC-/ARV7-, CTC+/ARV7-, CTC+/AR+ groups. RESULTS: PSA-RR shown ≥30% was 38%(18/48) and ≥50% was 26%(12/48). BSI-change rate shown ≥-30% was 19%(9/41) and ≥-50% was 17%(8/41). Median OS was 13.7(12.2–18.9) months. PSA decline in early CBZ treatment associated with OS(p=0.00173). BSI decline associated with OS(p=0.0194). PSA-RR(≥50%) was 21%(3/14) in CTC-/ARV7- group, 16%(4/25) in CTC+/ARV7- and 12%(1/8) in CTC+/ARV7+. No statically significant differences between groups. AR-V7 in CTCs at baseline not associated with OS. CONCLUSIONS: AR-V7 in CTCs was not associated with resistance to CBZ. BSI and PSA reducing responses in early CBZ may predict OS.
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