Efficacy Of Cabazitaxel Research Articles

The role of Cabazitaxel in patients with castration-resistant and osseous metastases prostate cancer. A Hellenic Cooperative Oncology Group Phase II Study.: Cabazitaxel in mCRPC patients with osseous metastases

BackgroundCabazitaxel is an effective treatment in metastatic castration-resistant prostate cancer (mCRPC) patients previously exposed to docetaxel and novel hormonal treatments. Understanding the molecular biology of mCRPC disease and taking into account the several approved treatment options, biomarkers are needed to guide decision making including cabazitaxel treatment. MethodsCababone was a phase II translational study that attempted to identify predictors of cabazitaxel efficacy. mCRPC with documented bone metastases were enrolled prospectively and treated with cabazitaxel 25mg/m2 every three weeks. Prostate cancer biopsies, bone marrow aspirates and blood samples were collected for translational research. ResultsSixty patients were enrolled and 59 received treatment according to protocol. Six-month progression free survival (PFS) rate was 47% (95% CI: 33% - 59%) and 12-month Overall Survival (OS) rate was 70% (95% CI: 56% - 80%). Patients with reactive hematopoiesis had improved PFS and OS with cabazitaxel treatment. Mutations in HRR genes were detected in 7 patients. ConclusionsNo differences in cabazitaxel efficacy were noted according to mutational status of HRR genes analyzed. No new safety issues were detected. In conclusion, CabaBone confirmed efficacy of cabazitaxel in mCRPC patients including the subgroup of patients with HRR mutations. Reactive hematopoiesis in bone marrow biopsies was related to improved survival warranting further investigation of bone biomarkers as predictors of cabazitaxel efficacy. Micro-AbstactCabaBone is a phase II translational study that evaluated the role of bone microenvironment and HRR genes mutations in the efficacy of cabazitaxel in mCRPC patients with bone-only disease. Study confirmed efficacy of cabazitaxel in patients independent of the presence of HRR gene mutations. Reactive hematopoiesis in bone marrow was recognized as a possible predictive and prognostic biomarker of cabazitaxel efficacy.

The Efficacy of Cabazitaxel in Treating Prostate Cancer: A Systematic Review and Meta-Analysis.

Cabazitaxel, a second-generation taxane chemotherapy agent, has demonstrated efficacy in treating metastatic castration-resistant prostate cancer (mCRPC) in patients who have previously received docetaxel-based therapy. By targeting microtubule dynamics, cabazitaxel inhibits cancer cell division and induces apoptosis, thereby extending survival and delaying disease progression in this challenging patient population. A systematic review and meta-analysis were done by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software. Our research reveals significantly improved outcomes in terms of patient survival rates, both progression-free survival (PFS) and overall survival (OS), for cabazitaxel over comparative treatment (PFS HR 0.77 [0.61, 0.97]) (OS HR 0.79 [0.70, 0.88]). The treatment response rates were also favorable for cabazitaxel, reported as PSA Reduction Response of more than 50% (PRR) (odds ratio (OR) = 1.59 [0.56, 4.52]) and tumor response rate (TRR) (OR = 2.34 [1.28, 4.28]). Cabazitaxel was associated with significantly more incidence of adverse events. The risk ratio (RR) for serious adverse events was 1.64 [1.14, 2.35] for cabazitaxel compared to the current regimen. A systematic review and meta-analysis were done by searching in the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE (including MEDLINE InProcess; OvidSP), Web of Science, Embase (OvidSP), and Scopus databases. ROB2 Cochrane tools assessment for RCTs. In the analysis, we used RevMan Cochrane software.

A novel cabazitaxel liposomes modified with ginsenoside Rk1 for cancer targeted therapy

Objective: In this study, we aim to enhance the anti-prostate cancer efficacy of cabazitaxel (CTX) and reduce its immunosuppression and systemic toxicity by developing CTX-loaded liposomes modified with ginsenoside Rk1 (Rk1/CTX-Lip). Methods: Physical and chemical properties of Rk1/CTX-Lip were investigated. We evaluated the biological functions of Rk1/CTX-Lip, both in vitro and in vivo. A subcutaneous prostate cancer (RM-1)-bearing mouse model was established to study the efficacy of Rk1/CTX-Lip inhibition in tumors. Simultaneously, a Candida albicans infection model was established in tumor-bearing mice to study the infection-relieving efficacy of Rk1/CTX-Lip. Finally, biocompatibility and in vivo safety of Rk1/CTX-Lip were evaluated. Results: We successfully prepared Rk1/CTX-Lip, achieving high CTX encapsulation efficiency (97.24 ± 0.75)% and physical stability. Rk1/CTX-Lip demonstrated evasion of macrophage phagocytosis, effective tumor tissue targeting, and a significant reduction (>50%) in average tumor volume compared with Chol/CTX-Lip. Moreover, it relieved the concurrent infection burden and effectively regulated immune organs and cells, demonstrating superior biocompatibility. Conclusion: Rk1/CTX-Lip presents a promising new therapy for prostate cancer and holds potential for relieving concurrent fungal infections in cancer patients with low immunity.

Pretreatment of prostate cancer cells with salinomycin and Wnt inhibitor increases the efficacy of cabazitaxel by inducing apoptosis and decreasing cancer stem cells.

Cancer stem cells (CSCs) are associated with metastasis and recurrence in prostate cancer as well as other cancers. We aimed to enhance the sensitivity of cabazitaxel in prostate cancer cell therapy by targeting CSCs with a Wnt inhibitor and salinomycin pretreatment. PC3, DU-145, and LNCaP human prostate cancer cells were exposed to Wnt/β-catenin pathway inhibitor CCT036477 (iWnt) with salinomycin for 48h, followed by cabazitaxel treatment for 48h. Cell viability, mRNA, and protein expression changes were evaluated by MTT, RT-qPCR, and Western blot assays, respectively. Apoptosis was determined by image-based cytometry, and cell migration was assessed by wound healing assay. Three-dimensional culture was established to assess the malignant phenotype and stemness potential of transformed or cancer cells. CD44 + CSCs were isolated using magnetic-activated cell sorting system. Pretreatment of PC3, DU-145, and LNCaP cells with salinomycin iWnt significantly sensitized the cells to cabazitaxel therapy. Spheroid culture confirmed that the treatment modality was more effective than a single administration of chemotherapy. The pretreatment of PC3 cells increased the rate of apoptosis compared to single administration of cabazitaxel, which downregulated Bcl-2 and upregulated caspase 3, caspase 8 expressions. The pretreatment suppressed cell migration, downregulated the expression of Sox2 and Nanog, and significantly reduced CD44 + CSC numbers. Notably, the treatment modality reduced pAKT, p-P38 MAPK, and pERK1/2. The data suggest that pretreatment of prostate cancer cells with salinomycin and Wnt inhibitor may increase the efficacy of cabazitaxel therapy by inhibiting cell proliferation and migration, and eliminating cancer stem cells.

Cytotoxic Effect of 6-Ethyl-Chenodeoxycholic Acid and Cabazitaxel on PC-3 Cells

Introduction. Chemotherapy with Cabazitaxel (CBZ) is a typical first-line treatment option for naïive castration-resistant prostate cancer resistant to docetaxel. On the other hand, Cabazitaxel's therapeutic success is constrained by chemoresistance and side effects.Aim. To assess whether 6 alpha-ethylchenodeoxycholic acid (6-ECDCA), a selective agonist for bile acid receptors will enhance the efficacy of CBZ in androgen-independent prostate cancer cells.Materials and methods. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay was used to assess the cytotoxicity of 6-ECDCA and CBZ medicines or their combinations against the human prostate cancer cell line (PC-3). The combination outcome suggested by Chou TC et al. was then evaluated using the combination index (CI) to find out the nature of synergism, antagonism, and additive effect of the drug’s combination. Furthermore, the Dose-Reduction Index (DRI) was determined to measure how many times the dose could be reduced for each drug in a synergistic combination.Results and discussion. Analysis of the dose-effect curve showed that the treatment of PC-3 cells with CBZ alone or combined with 6-ECDCA for 48 h led to 50 % cytotoxicity of 20.5 nM and 4.7 nM, respectively. 6-ECDCA at 1.77 µM had an additive effect based on the CI value, which was 1.02, while at 21.02 µM, the CI was 0.54 which designates a strong synergistic effect. The combination of CBZ and 6-ECDCA at a submaximal lower dose by 6-folds of each one produced a 95 % cell death than treatment with either agent alone.Conclusion. The Combination index plot showed CI ≤ l for all combinations used in this study, which indicates additive and synergistic interactions between CBZ and 6-ECDCA. The significant impact of 6-ECDCA in combination with CBZ for treating androgen-independent prostate cancer cells was confirmed by this study to be preferred to the treatment with a single drug.

LuCAB: A phase I/II trial evaluating cabazitaxel in combination with [177Lu]Lu-PSMA-617 in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC)

TPS278 Background: [177Lu]Lu-PSMA-617 was recently FDA-approved for use in the post-taxane, post-antiandrogen setting in pts with mCRPC. Despite conferring a survival benefit, for many the treatment response is short, and progression is inevitable. One of the likely mechanisms limiting the durability of responses to [177Lu]Lu-PSMA-617 is heterogeneity in tumor PSMA expression. This can be screened for visually using PSMA and FDG PET/CT scans and inspecting for discordant disease, however, micrometastatic disease is unable to be evaluated in this way. In addition, [177Lu]Lu-PSMA-617 may not effectively target micrometastatic disease due to the longer path length of beta emitters. Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of [177Lu]Lu-PSMA-617, whilst also treating any PSMA-negative disease. We hypothesize that the combination of [177Lu]Lu-PSMA-617 and cabazitaxel will be well tolerated and lead to more durable responses. Methods: This single-centre, single-arm phase I/II trial will enrol 32-38 pts with mCRPC to evaluate the safety and preliminary efficacy of cabazitaxel and [177Lu]Lu-PSMA-617 in combination. Up to 6 doses of [177Lu]Lu-PSMA-617 (7.4 GBq) will be administered intravenously every 6 weeks. Cabazitaxel will be given concurrently (dose range 12.5mg/m2 - 20mg/m2), on Day 2 and Day 23 of each 6-week cycle. The dose of cabazitaxel will be escalated using a traditional 3+3 design. Key eligibility criteria include a diagnosis of mCRPC with PSMA-positive disease on PSMA PET/CT (SUVmax ≥15), with no evidence of diffuse marrow disease or sites of discordance on FDG PET/CT. Pts must have progressed after prior docetaxel and a second-generation antiandrogen, have adequate bone marrow and organ function and an ECOG performance status of 0-1. The primary objective is to establish the maximum tolerated dose of cabazitaxel and [177Lu]Lu-PSMA-617. Secondary objectives include measuring the frequency and severity of adverse events, assessment of efficacy through PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective tumor response rate, and evaluation of pain and health-related quality of life over the first 12 months. Bloods will be taken at baseline, during treatment and at progression for ctDNA analysis, the results of which will be correlated with baseline pt and disease characteristics, and response outcomes, to determine biomarkers of treatment response and resistance. Pt recruitment commenced in August 2022 and will continue for 18 months. Clinical trial information: NCT05340374 .

The Bristol Bladder Trial: Five year outcomes in patients treated with neoadjuvant cabazitaxel and cisplatin chemotherapy for muscle invasive transitional cell carcinoma of the urinary bladder.

493 Background: Neoadjuvant cisplatin-based combination chemotherapy (NAC) improves survival in muscle invasive bladder cancer (MIBC). However, response rates and survival remain suboptimal. We sought to evaluate the efficacy of cabazitaxel with cisplatin in this patient group. These patients have now been followed for survival status for 5 years post NAC and radical cystectomy. Methods: This was a single arm (Simon 2 stage), phase 2 study. Patients with MIBC were included if fit to receive NAC and to undergo radical cystectomy. 26 evaluable patients were required to detect an objective response rate (ORR) of >35% with 80% power. ORR was defined as pathological complete response (pCR) plus partial response (pathological downstaging, ≥T2 at diagnosis to ≤T1 at cystectomy). Treatment was with cisplatin 70mg/m2 and cabazitaxel 15mg/m2 on day 1 of a 21-day cycle, for 4 cycles prior to surgery. Toxicity was recorded using CTCAE v.4.03. QoL data was assessed during and after chemotherapy using EQ-5D-5L and EORTC-QLQ-C30, BLM30 questionnaires. Patients were followed for 5 years post cystectomy for progression free survival (PFS) and overall survival (OS). Results: ORR was seen in 15 out of 26 evaluable patients, 57.7%, with 24.6% achieving pCR. 1 out of 15 patients who achieved ORR died due to disease progression in the 5 year follow up period. The median PFS and OS were not reached by the 5 year follow up time point with a 5 year survival rate of 65.4% being seen in this patient cohort. Median OS in non-responders (11 patients) was 20.5 months and 5 year survival rate for the non-responders was 36.4% compared to 93.3% for responders. Conclusions: Neoadjuvant cabazitaxel with cisplatin chemotherapy is an effective regimen with 65.4% patients alive and progression-free at 5 years. It also indicates that ORR (and not just pCR), is a good predictor of patient survival at 5 years post radical cystectomy with only 1 out of 15 patients who achieved ORR progressing and dying in this period. However, in current clinical practice, there are no validated predictive biomarkers regarding potential response to NAC. Taken together with our previously published data, cabazitaxel with cisplatin as neoadjuvant chemotherapy is a safe, well-tolerated and effective regimen and should be compared to the regimens e.g. cisplatin/gemcitabine considered as standard in this setting. Clinical trial information: NCT01616875 .

Efficacy of cabazitaxel and androgen splicing variant-7 status in circulating tumor cells in Asian patients with metastatic castration-resistant prostate cancer

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.

Efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer: A single-center study in Japan.

Cabazitaxel is a next-generation taxane that can prolong overall survival after docetaxel treatment in patients with metastatic castration-resistant prostate cancer. However, the efficacy of cabazitaxel varies among these patients. The clinical indicators of the prognosis after cabazitaxel treatment were analyzed. A retrospective review of patients who received cabazitaxel between February 2015 and June 2021 was performed. All patients had metastatic castration-resistant prostate cancer. Prognostic factors for prostate-specific antigen progression-free and overall survival were analyzed by Cox proportional-hazards analysis and the log-rank test. The study comprised 57 patients who received cabazitaxel (median 4 cycles, range 1-27) at a starting dose of 15-25 mg/m2 . The median age and follow-up duration were 70 years and 9.2 months. The median prostate-specific antigen progression-free survival and overall survival were 2.6 and 10.5 months, respectively. Univariate analysis showed that previous androgen receptor-axis-targeted therapy before cabazitaxel treatment was the only significant risk factor (hazard ratio 2.784, p = 0.022) for prostate-specific antigen progression-free survival. Multivariate analysis for overall survival revealed that poor performance status (≥1) (hazard ratio 2.107, p = 0.039), low hemoglobin (hazard ratio 0.142, p = 0.010), and high neutrophil-lymphocyte ratio (hazard ratio 9.150, p = 0.032) at baseline were significantly associated with a poor prognosis. Previous androgen receptor-axis-targeted therapy was the only risk factor for biochemical progression. Poor performance status, anemia, and high neutrophil-lymphocyte ratio were risk factors for poor prognosis in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel. These risk factors seem useful for identifying patients with survival benefit from cabazitaxel treatment.

Long-term outcomes of a randomized controlled clinical trial comparing the efficacy of cabazitaxel versus docetaxel as second-line or above therapy in recurrent head and neck cancer.

e18008 Background: Long term outcomes (> 2 years or above) are rarely reported in studies with second line or beyond systemic therapies in head and neck squmouas cell carcinoma (HNSCC). Methods: Recurrent or relapsed adult HNSCC, with ECOG PS 0-2 who have been exposed to at least one line of chemotherapy were 1:1 randomized between Docetaxel (75 mg/m2) and Cabazitaxel (20 mg/m2). The chemotherapy was given till progression or development of intolerable side effects. The outcomes reported are long term overall survival(OS) and progression free survival (PFS) and factors impacting overall survival. Results: On the intention to treat analysis (n = 92), at the time of data censoring, 92 patients had died. The median overall survival was 112 days (95% CI 81 to 178 days) in the cabazitaxel arm versus 192 days (95% CI 153 to 259 days) in the Docetaxel arm (P = 0.048). In cabazitaxel arm, the one year OS was 6.5% (95% CI 1.6-16.06), 2 year OS was 2.17% (95% CI 0.17-9.95) and 3 years was 2.17% (95% CI 0.17-9.95). While the corresponding figures in the docetaxel arm were 21.7% (95% CI 11.23-34.46), 0% and 0%. The median progression-free survival was 21.0 days (95% CI 16.0-42.0 days) in the Cabazitaxel arm versus 57.5 days (95% CI 26.0-85.0 days) in the Docetaxel arm (P = 0.02). Among the tested factors age (p = 0.037) and site of primary(p = 0.023) had an impact on OS. Conclusions: In this phase 2 randomised study, cabazitaxel has inferior PFS and OS than docetaxel. Hence docetaxel remains the option of choice when cytotoxic chemotherapy needs to be used as second line or beyond setting in HNSCC. Clinical trial information: CTRI/2015/06/005848.

Influence of darolutamide on cabazitaxel systemic exposure.

5038 Background: Taxane efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients is limited due to resistance development. In preclinical models it has been shown that addition of the androgen receptor signalling inhibitor (ARSI) enzalutamide improves cabazitaxel efficacy. However, we have previously shown that the clinical utility of this combination is hampered by a strong CYP3A4 drug-drug interaction with enzalutamide, resulting in a 22% reduced cabazitaxel systemic exposure. Darolutamide has much weaker CYP3A4 inducing effects and therefore may affect cabazitaxel systemic exposure to a lesser extent. Methods: We investigated the influence of darolutamide on cabazitaxel plasma exposure. mCRPC patients were enrolled on cabazitaxel monotherapy (20 mg/m2 Q3W) on day 1 and received concomitant darolutamide (600 mg b.i.d.) from day 2 onwards for maximal 12 weeks. During cabazitaxel infusion on day 1, and after 6 and 12 weeks of darolutamide treatment, we measured cabazitaxel systemic exposure via Area Under the Curve from 0 to 24 hours (AUC0-24h). Results: Cabazitaxel systemic exposure in 18 patients after 6 weeks of darolutamide was not significantly different compared to prior to darolutamide treatment (AUC0-24h: -4%; 95%CI -19 – +13%; p = 0.58). Also, after 12 weeks of darolutamide treatment, cabazitaxel systemic exposure was unaltered (AUC0-24h: +4%; 95%CI -10 – +20%; p = 0.54). Darolutamide plasma concentrations were constant throughout the study (Table). Conclusions: From a pharmacokinetic perspective cabazitaxel and darolutamide can be safely combined in mCRPC patients. Our findings pave the way for testing the efficacy of this promising combination in an era of combination regimens for prostate cancer. Clinical trial information: NL8611. [Table: see text]

Continued androgen signalling inhibition improves cabazitaxel efficacy in prostate cancer.

Background: The androgen receptor (AR) pathway is a key driver of neoplastic behaviour in the different stages of metastatic prostate cancer (mPCa). Targeting the AR therefore remains the cornerstone for mPCa treatment. We have previously reported that activation of AR signalling affects taxane chemo-sensitivity in preclinical models of castration resistant PCa (CRPC). Here, we explored the anti-tumour efficacy of the AR targeted inhibitor enzalutamide combined with cabazitaxel.Methods: We used the AR positive CRPC model PC346C-DCC-K to assess the in vitro and in vivo activity of combining enzalutamide with cabazitaxel. Subsequent validation studies were performed using an enzalutamide resistant VCaP model. To investigate the impact of AR signalling on cabazitaxel activity we used quantitative live-cell imaging of tubulin stabilization and apoptosis related nuclear fragmentation.Findings: Enzalutamide strongly amplified cabazitaxel anti-tumour activity in the patient-derived xenograft models PC346C-DCC-K (median time to humane endpoint 77 versus 48 days, P<0.0001) and VCaP-Enza-B (median time to humane endpoint 80 versus 53 days, P<0.001). Although enzalutamide treatment by itself was ineffective in reducing tumour growth, it significantly suppressed AR signalling in PC346C-DCC-K tumours as shown by AR target gene expression. The addition of enzalutamide enhanced cabazitaxel induced apoptosis as shown by live-cell imaging (P<0.001).Interpretation: Our study demonstrates that cabazitaxel efficacy can be improved by simultaneous blocking of AR signalling by enzalutamide, even if AR targeted treatment no longer affects tumour growth. These findings support clinical studies that combine AR targeted inhibitors with cabazitaxel in CRPC.

Efficient delivery of hydrophobic drug, Cabazitaxel, using Nanodisc: A nano sized free standing planar lipid bilayer

Several new drug candidates have emerged as potential cancer therapeutics with the advent of drug discovery. The hydrophilic drug candidates have easily translated to chemotherapy via oral or intravenous administration methods, whereas efficient drug delivery vehicles for hydrophobic drugs have been an area of concern. This has resulted in an increasing interest in the nano-sized polymer and lipid-based drug delivery systems due to their enhanced distribution, bioavailability, and therapeutic value. In this study, the efficiency of membrane scaffold protein (MSP) embedded POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine) nanodiscs has been investigated as a hydrophobic drug delivery vehicle. Synthesized nanodiscs with an average diameter of 27.03 ± 1.5 nm were loaded with different hydrophobic drugs and evaluated for biocompatibility and drug release kinetics. The drug loading was found to be proportional to the hydrophobicity (LogP) of the drugs. Drug loaded nanodiscs showed sustained drug release till 24 h which was preceded by initial burst release. Drug delivery efficacy of cabazitaxel loaded nanodiscs (NDCBT) was tested by in vitro cytotoxicity assay, cell cycle arrest analysis, and spheroid growth inhibition study. We achieved significant enhancement of autophagy mediated cell death using NDCBTs when compared to free drug. Similarly, NDCBTs were able to induce approximately 20% higher toxicity in 3D spheroids model.

P0441 - Cabazitaxel efficacy is strongly enhanced by continued Androgen Receptor Targeted Agents (ARTA) in Castration-Resistant Prostate Cancer (CRPC)

P0441 - Cabazitaxel efficacy is strongly enhanced by continued Androgen Receptor Targeted Agents (ARTA) in Castration-Resistant Prostate Cancer (CRPC)

Indirect treatment comparison of the efficacy of olaparib 300 mg tablets BID and cabazitaxel 25 mg/m2 every 3 weeks plus daily prednisolone and granulocyte colony-stimulating factor in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

5051 Background: In PROfound, olaparib demonstrated improved radiological PFS (rPFS) and overall survival (OS) versus new hormonal agent (NHA) in patients with homologous recombination repair mutated (HRRm) mCRPC that had progressed on prior NHA. This efficacy was observed across prespecified subgroups including patients treated with prior taxane therapy and for whom intravenous cabazitaxel is an alternative treatment option. The relative efficacy of olaparib versus cabazitaxel has not been assessed in head-to-head studies. An indirect treatment comparison (ITC) was performed to simulate the comparative efficacy of olaparib and cabazitaxel in patients with HRRm mCRPC after prior taxane and NHA. Methods: Fixed-effects frequentist ITCs were conducted using efficacy data from the prior taxane subgroup of PROfound (NCT02987543) and published data from the Phase IV CARD study of cabazitaxel versus NHA after prior NHA and taxane treatment (NCT02485691). Baseline variables feasible for comparison across studies were assessed for effect modification. Efficacy analyses were performed on the hazard ratios (HR) of rPFS by independent central review and OS. The OS analysis was performed using the final PROfound OS results, which included switching from NHA to olaparib after progression, and using results that were adjusted for switching. In the absence of biomarker subgroup data, the efficacy results of the overall population in CARD were assumed generalizable to the HRRm biomarker population of PROfound, such that mutation status is not a modifier of relative treatment effect for cabazitaxel versus NHA. Results were presented for the comparison of olaparib with cabazitaxel in the BRCA1-/BRCA2-mutated (BRCAm) and BRCAm/ATM populations. Results: The ITC HR for rPFS was 0.36 (95% confidence interval 0.20–0.64) in BRCAm and 0.51 (0.31–0.84) for the BRCAm/ATM population. Without adjustment for switching in PROfound, the ITC HRs for OS in the BRCAm population and BRCAm/ATM population were 0.99 (0.55–1.78) and 0.88 (0.52–1.47), respectively; after switch adjustment, the OS HRs were 0.47 (0.12–1.79) and 0.44 (0.17–1.10), respectively. Conclusions: The ITC results suggest that olaparib is associated with significantly improved rPFS versus cabazitaxel in the treatment of BRCAm and BRCAm/ATM patients who have progressed on taxane and NHA therapy. After removing the effect of switching from NHA to olaparib in PROfound, olaparib appears associated with a non-significant OS improvement versus cabazitaxel in both populations. The results require confirmation in comparative studies. Analysis limitations include uncertainty over the efficacy of cabazitaxel versus NHA in HRRm mCRPC patients, and heterogeneity in prior taxane and NHA therapy. Clinical trial information: NCT02987543.

Association between the anticancer efficacy of cabazitaxel and toll-like receptor 4 mediating signaling pathways in metastatic castration-resistant prostate cancer cells.

We evaluated the effect of cabazitaxel (CAB) as a third-line taxane on Toll-like receptor 4 (TLR4)-mediated signaling pathways, especially NF-κB activity, in metastatic castration-resistant prostate cancer (mCRPC) cells. CAB cytotoxicity was determined by WST-1 assay. To assess the relationship between CAB efficacy and TLR4 signaling pathways, RT-PCR, western blot and immunofluorescence analysis were performed. Additionally, CAB-mediated apoptotic cell death was assessed by Annexin V and RT-PCR analysis. Our results demonstrated that CAB exerted considerably cytotoxic and apoptotic effects on PC-3 mCRPC cells (p < 0.05). CAB treatment altered TLR4 expression level in a dose-dependent manner. Furthermore, 1 nM CAB treatment significantly induced NF-κB activity through p65 nuclear localization and increased the expression level of caspase-3, Bax and p53. Interestingly, total apoptotic cell death and IRF3 protein levels were increased at 5 nM concentration of CAB despite a decrease in the levels of both NF-κB and pro-apoptotic genes. Therefore, NF-κB activity may be a potential target for the efficacy of CAB in mCRPC cells.

Efficacy of cabazitaxel and the influence of clinical factors on the overall survival of patients with castration-resistant prostate cancer: A local experience of a multicenter retrospective study.

To date, the optimal sequencing of life-prolonging therapies for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unclear owing to a lack of prospective trials. This study aimed to evaluate the efficacy and safety of cabazitaxel (CBZ) treatment and examine the prognostic factors for oncological outcomes in patients with mCRPC who received CBZ after docetaxel (DOC). This multi-institutional retrospective study included 44 patients with mCRPC who received CBZ. All enrolled patients had histologically confirmed prostate cancer (PCa) with distant metastases and had received DOC before CBZ administration. The primary endpoint was the oncological outcomes, including the overall (OS) and progression-free survival (PFS). The secondary endpoints were adverse events due to CBZ and rates of ≥30% reduction in prostate-specific antigen (PSA) levels. The median follow-up period was 9.2 months (range, 0.2-34 months). During this time, 34 patients (77%) died of PCa. The median OS and PFS were 12.2 (range, 0.2-34 months) and 1.4 months (range, 0.4-17 months), respectively. According to the PSA decline rate, patients who achieved a ≥30% reduction in PSA levels had significantly longer OS than those who showed a<30% reduction in PSA levels (P=0.002). Regarding the number of cycles of CBZ, patients who received ≥4 cycles of CBZ showed significantly longer OS than those who received<4 cycles of CBZ (P<0.001). Patients who had visceral metastasis showed significantly shorter OS than those without visceral metastasis (P=0.012). This study demonstrated that CBZ was effective and safe in Japanese local patients in a real-world setting. Patients with mCRPC who received ≥4 cycles of CBZ showed a ≥30% reduction in the serum PSA levels, and did not have visceral metastasis might achieve longer OS.

Ultrasound-Mediated Delivery of Chemotherapy into the Transgenic Adenocarcinoma of the Mouse Prostate Model

Ultrasound (US) in combination with microbubbles (MB) has had promising results in improving delivery of chemotherapeutic agents. However, most studies are done in immunodeficient mice with xenografted tumors. We used two phenotypes of the spontaneous transgenic adenocarcinoma of the mouse prostate (TRAMP) model to evaluate if US + MB could enhance the therapeutic efficacy of cabazitaxel (Cab). Cab was either injected intravenously as free drug or encapsulated into nanoparticles. In both cases, Cab transiently reduced tumor and prostate volume in the TRAMP model. No additional therapeutic efficacy was observed combining Cab with US + MB, except for one tumor. Additionally, histology grading and immunostaining of Ki67 did not reveal differences between treatment groups. Mass spectrometry revealed that nanoparticle encapsulation of Cab increased the circulation time and enhanced the accumulation in liver and spleen compared with free Cab. The therapeutic results in this spontaneous, clinically relevant tumor model differ from the improved therapeutic response observed in xenografts combining US + MB and chemotherapy.

Real-world efficacy and safety of two doses of cabazitaxel (20 or 25\u2009mg/m2) in patients with castration-resistant prostate cancer: results of a Japanese post-marketing surveillance study

BackgroundThe recommended starting dose of cabazitaxel for castration-resistant prostate cancer (CRPC) is 25 mg/m2 in Japan and Europe. Although lower doses are established alternatives based on randomized controlled trials, the safety and efficacy of 25 and 20 mg/m2 in real-world settings are not well established. Therefore, we investigated the safety and efficacy of cabazitaxel at the recommended starting dose or a lower dose (20 mg/m2) in real-world clinical practice.MethodsWe compared the safety and efficacy of cabazitaxel between patients who received cabazitaxel at starting doses of 25 and 20 mg/m2 (C25 and C20, respectively) in a Japanese post-marketing surveillance study of 662 patients with docetaxel-refractory CRPC. Safety was assessed in terms of adverse drug reactions (ADRs). Prostate-specific antigen (PSA) response rate, overall survival (OS), and time-to-treatment failure (TTF) were compared between the C25 and C20 groups in unmatched patients and after applying propensity score matching.ResultsThe C20 and C25 groups comprised 190 and 159 patients without matching and 112 patients per group after matching. In unmatched patients, any-grade (C25 vs C20: 89.3% vs 78.4%, Fisher’s p < 0.01) and grade ≥ 3 (81.1% vs 61.1%) ADRs were more frequent in the C25 group. Neutropenia (any grade: 61.6% vs 54.2%; grade ≥ 3: 55.3% vs 42.6%) and febrile neutropenia (grade ≥ 3: 30.2% vs 14.7%) were more frequent in the C25 group. In matched patients, the PSA response rate (reduction in PSA ≥30% from a baseline ≥5 ng/mL) was 26.4 and 32.0% in the C20 and C25 groups, respectively, median OS was 291 days (95% CI 230–not reached) versus not reached (hazard ratio 0.73, 95% CI 0.50–1.08), and TTF favored C25 (hazard ratio 0.75, 95% CI 0.57–0.99).ConclusionsClinicians should consider the patient’s risk of clinically significant ADRs and prophylactic granulocyte colony stimulating factor when selecting the starting dose of cabazitaxel for CRPC. Some patients at high risk of ADRs or unfit patients may benefit from a lower starting dose of 20 mg/m2, whereas fit patients may be candidates for a starting dose of 25 mg/m2.Trial registrationNot applicable.

Single nucleotide polymorphisms (SNPs) as predictors of efficacy of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC).

e17582 Background: Cabazitaxel is a semi-synthetic derivative of a natural taxoid approved for the treatment of mCRPC patients (pts) after failure to docetaxel. Despite its proven efficacy, there is variability in the response, progression-free survival (PFS) and overall survival (OS) of pts. Changes in the genetic constitution of the individual such as the SNPs could explain this variability. The aim of this study was to evaluate the impact of certain SNPs in cabazitaxel activity. Methods: Clinical data from 67 mCRPC pts treated with cabazitaxel between March 2011 and October 2016 were collected. DNA was isolated from formalin fixed paraffin-embedded tumor samples. 56 SNPs in 5 genes related with metabolism and/or mechanism of action of cabazitaxel (CYP3A4, CYP3A5, ABCB1, TUBB1, CYP2C8) were chosen based on their Minor Allele Frequency, linkage disequilibrium and information from dbSNP and analyzed by TaqMan OpenArray (Lifetech). The presence/absence of mutant alleles of the selected SNPs was correlated with clinical features, progression free survival (PFS) and overall survival (OS) of prostate cancer. Chi-square test and Kaplan-Meier with log-rank test were used for statistical analyses. Results: The median age was 61 years (range 44-82). 56.7% (n = 38) had a Gleason score ≥8 and 94% had received docetaxel in first line. Type of response to cabazitaxel was associated with median OS (Partial response = 24.35 months, Stable disease = 11.16 months, Progression disease = 5.8 months; p= 0.045). Univariate analysis, showed worsed OS at 1 year for wild type status of SNP rs151352 (OR = 4, 95%CI 1.27-12.58, p= 0.029). In addition, two SNPs (rs11773597, rs1202186) were associated with radiological response to cabazitaxel ( p= 0.031 and p= 0.030 respectively). Other 7 SNPs (rs11773597, rs2235040, rs1045642, rs1419745, rs1202170, rs6949448, rs11572093) were associated ( p&lt;0.05) with Gleason score, pain, PSA doubling time, febrile neutropenia and asthenia. Conclusions: A particular SNP profile could be predictive of efficacy and related with toxicity in mCRPC population treated with cabazitaxel after progression to docetaxel. These outcomes become particularly relevant in patient selection given the recent results of the CARD trial.