Cycles Of Cabazitaxel Research Articles

Efficacy and safety of dendrimer-enhanced (DEP) cabazitaxel (CTX-SPL9111) in advanced esophagogastric cancers in a phase 1/2 trial.

374 Background: There is a significant unmet need in esophagogastric cancers (EGC) due to limited effective treatments (Tx) and poor prognosis. Dendrimers are highly branched nanoparticles that enable sustained delivery of cytotoxic drugs and achieve selective tumor targeting via an enhanced permeability and retention effect. DEP cabazitaxel is a highly optimised dendrimer formulation of cabazitaxel. Unlike standard cabazitaxel, DEP cabazitaxel is highly water soluble, does not contain toxic excipients such as polysorbate-80 associated with anaphylaxis, and avoids the need for steroid/antihistamine pre-medication. The objective of this Phase 1/2 trial was to assess preliminary efficacy and safety of DEP cabazitaxel in patients (pts) with advanced solid tumors including EGC, for which standard cabazitaxel is not approved. Methods: In the P2 part of the trial, advanced EGC pts with measurable disease were treated with DEP cabazitaxel 20 mg/m2 cabazitaxel, the recommended Phase 2 dose, IV 3-weekly. Anti-tumour activity was assessed by RECIST v1.1, safety by CTCAE v4.03. (EudraCT 2017-003424-76). Results: Fifteen pts with advanced EGC were enrolled; 9 adenocarcinoma (ADENOCA) (3 gastric, 2 esophageal and 4 EG junction) and 6 esophageal squamous cell carcinoma (ESCC); median age 62 yrs (26–73 yrs), with all pts having ≤3 prior anticancer Tx, and the majority (9) having progressed on or immediately after 1st line Tx (1L). All had ≥1 prior platinum-based regimen and 4 pts had received prior taxanes. Pts received a median of 4.5 DEP cabazitaxel cycles without the need for routine steroid/antihistamine or primary G-CSF prophylaxis. In all evaluable pts, disease control rate (DCR) was 80%. Disease control was observed in both histological subtypes and was durable, including stable disease (SD) for up to 27 weeks and partial responses (PR) for up to 17 weeks, with objective response rate (ORR) of 30%. In EG ADENOCA pts, DCR was 100%, ORR was 33%, and median progression free survival (mPFS) was 4.0 months. In ESCC pts, DCR was 50% and ORR was 25%, with mPFS of 1.9 months. DEP cabazitaxel was well-tolerated with mostly mild (62.9%, Grade (G) 1)/moderate (20.2%, G2) treatment-related adverse events (TRAEs), including nausea, vomiting, fatigue, neuropathy, neutropenia (only 1 pt had G-CSF Tx, 1 pt had secondary G-CSF prophylaxis) and anemia, that were like those observed with standard cabazitaxel Tx. Of severe TRAEs (G3/4; 16.9%) most (80%) were observed in 2 pts, including neutropenia, anemia, thrombocytopenia, fistula, elevated liver enzymes. Conclusions: DEP cabazitaxel exhibited highly encouraging anti-tumor activity in >1L, advanced EGC in multiple anatomic locations and of different histological sub-types. The preliminary efficacy and safety results compare favorably to available treatment options and highlight the promising clinical potential of DEP cabazitaxel in advanced EGC. Clinical trial information: EudraCT 2017-003424-76 .

Combined Cabazitaxel and Carboplatin Treatment of Metastatic Castration Resistant Prostate Cancer Patients, With Innate or Acquired Resistance to Cabazitaxel Monotherapy

BackgroundThere is new interest in platinum-based treatment of patients with metastatic castration resistant prostate cancer (mCRPC), to which a subgroup responds. Although platinum sensitivity is suggested to be associated with aggressive disease features and distinct molecular profiles, identification of responders is a clinical challenge. In this study, we selected patients who displayed PSA progression during cabazitaxel monotherapy, for combined cabazitaxel and carboplatin treatment. MethodsIn this retrospective study, mCRPC patients received carboplatin and cabazitaxel after biochemical progression following at least 2 cabazitaxel monotherapy cycles. We assessed PSA response, Time to PSA Progression (TTpsa) and Time to Radiographic Progression (TTrad). For a subset of patients, mutational analysis of BRCA-1, BRCA-2, ATM, PTEN, P53 and RB1 was performed. ResultsForty-five patients were included, after a median of 4 (3-6) cycles of cabazitaxel monotherapy. Patients received a median of 3 (2-5) cycles of combined cabazitaxel and carboplatin, on which 12 (26.6%) patients had a PSA decline ≥ 50% from baseline. TTpsa was 2 (1-5) months and TTrad 3 (2-6) months. Adverse events were predominantly grade 1-2. Of the 29 (64.4%) patients evaluable for molecular signature, 6 (13.3%) had BRCA1, BRCA2 or ATM mutations and 12 (26.7%) had a PTEN, P53 or RB1 mutations. The occurrence of these mutations was not associated with any clinical outcome measure. ConclusionsIn this study we showed that patients with PSA progression during cabazitaxel monotherapy could benefit from the addition of carboplatin to cabazitaxel, while prospective identification of these patients remains a clinical challenge.

Baseline characteristics may impact treatment duration of cabazitaxel in patients with mCRPC: a subanalysis of data from a post-marketing surveillance.

Cabazitaxel has demonstrated improvements in overall survival among patients with metastatic castration-resistant prostate cancer (mCRPC) in the pivotal comparison clinical trials TROPIC, PROSELICA and CARD. However, these trials include mCRPC patients with similar characteristics, and there are limited data on how baseline characteristics affect treatment discontinuation in the patient population. To assess individual factors that may impact the discontinuation rate of cabazitaxel treatment, we conducted a post hoc analysis of data from a nationwide all-case, post-marketing surveillance of cabazitaxel in Japan. Patients were grouped according to the number of cabazitaxel treatment cycles received (1-2 and≥3cycles). Predictive factors were identified through multivariate logistic regression analysis. Across 660 patients with metastatic castration-resistant prostate cancer, 70.2% received ≥3cycles of cabazitaxel treatment. Those receiving 1-2cycles of cabazitaxel had a greater proportion of patients with poorer Eastern Cooperative Oncology Group Performance Status, presence of lung and liver metastases, higher prostate-specific antigen level and prior radiation therapy at baseline. Regardless of the number of cabazitaxel cycles received, the primary reason for discontinuation was progression of disease rather than adverse events. Compared with those receiving 1-2cycles, a lower proportion of patients receiving 3-10 and≥11cycles of cabazitaxel treatment experienced adverse events. Multivariate analysis showed a significant association between early discontinuation and presence of liver lesions, poorer Eastern Cooperative Oncology Group Performance Status and higher prostate-specific antigen level at baseline. Post-marketing surveillance data suggest physicians should individualize cabazitaxel treatment based on certain patient characteristics at baseline.

Prognostic Role of Circulating Tumor Cells in Patients with Metastatic Castration-Resistant Prostate Cancer Receiving Cabazitaxel: A Prospective Biomarker Study.

Circulating tumor cells (CTCs) appear to be a promising tool for predicting the clinical outcome and monitoring the response to treatment in patients with solid tumors. The current study assessed the clinical relevance of monitoring CTCs in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel. Patients with histologically confirmed mCRPC who were previously treated with a docetaxel-containing regimen and experienced disease progression were enrolled in this multicenter prospective study. CTC counts were enumerated using the CellSearch system at baseline (before cabazitaxel initiation), after one cabazitaxel cycle (post 1st cycle) and at disease progression (PD). Patients were stratified into predetermined CTC-positive and CTC-negative groups. The phenotypic characterization was performed using double immunofluorescence staining with anti-CKs and anti-Ki67, anti-M30 or anti-vimentin antibodies. The median PFS and OS were 4.0 (range, 1.0-17.9) and 14.5 (range, 1.2-33.9) months, respectively. At baseline, 48 out of 57 (84.2%) patients had ≥1 CTCs/7.5 mL of peripheral blood (PB) and 37 (64.9%) had ≥5 CTCs/7.5 mL of PB. After one treatment cycle, 30 (75%) out of the 40 patients with available measurements had ≥1 detectable CTC/7.5 mL of PB and 24 (60%) ≥ 5CTCs/7.5 mL of PB; 12.5% of the patients with detectable CTCs at the baseline sample had no detectable CTCs after one treatment cycle. The detection of ≥5CTCs/7.5 mL of PB at baseline and post-cycle 1 was associated with shorter PFS and OS (p = 0.002), whereas a positive CTC status post-cycle 1 strongly correlated with poorer OS irrespective of the CTC cut-off used. Multivariate analysis revealed that the detection of non-apoptotic (CK+/M30-) CTCs at baseline is an independent predictor of shorter OS (p = 0.005). In patients with mCRPC treated with cabazitaxel, CTC counts both at baseline and after the first cycle retain their prognostic significance, implying that liquid biopsy monitoring might serve as a valuable tool for predicting treatment efficacy and survival outcomes.

Tumor Volume on PSMA PET as a Prognostic Biomarker in Prostate Cancer Patients Treated With Cabazitaxel.

The aim of this study was to evaluate the prognostic value of 68 Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT in metastatic castration-resistant prostate cancer patients receiving second-line chemotherapy with cabazitaxel. All patients with metastatic castration-resistant prostate cancer who underwent a PSMA PET/CT within 8 weeks before initiating the cabazitaxel treatment were retrospectively evaluated. The whole-body PSMA total tumor volume (PSMA-TV) was measured for each patient. Other factors such as prostate-specific antigen, hemoglobin, lactate dehydrogenase, and alkaline phosphatase were recorded. A log-rank cutoff finder was used to define the PSMA-TV optimal cutoff. Survival analyses were performed using Cox regression and Kaplan-Meier methods. In total, 32 patients were included, receiving a median of 6 cycles of cabazitaxel (range, 2-10). After a median follow-up of 12 months, 28 patients presented disease progression, and 18 died. Baseline PSMA-TV presented a significant association with progression-free survival (PFS) and overall survival (OS; P = 0.035 and P = 0.002, respectively). Optimal PSMA-TV cutoffs were 515 mL for PFS and 473 mL for OS. Patients with low volume presented longer PFS and OS than those with high volume: median PFS, 21 versus 12 weeks, respectively (hazard ratio, 0.33; P = 0.017); and median OS, 24 versus 8.5 months, respectively (hazard ratio, 0.21; P = 0.002). On the multivariable analyses, PSMA-TV remained an independent predictor of OS ( P = 0.016). Our results show that total tumor volume measured on PSMA PET/CT is a prognostic biomarker in patients treated with cabazitaxel. High PSMA-TV before treatment initiation is associated with shorter PFS and OS.

Transcriptomic analysis of plasma exosomes provides molecular information of response to cabazitaxel treatment in men with metastatic castration-resistant prostate cancer.

Prostate cancer is the second most common cancer type and the second most common cancer-related cause of death in men. Cabazitaxel, a next-generation taxane, shows favorable toxicity profile and is effective in docetaxel-resistant tumors. Despite initial responses, in most cases, prostate cancer patients acquire resistance to cabazitaxel. There is a need to identify molecular markers that can monitor and predict treatment response. We performed transcriptional exosome profiling (Human Transcriptome Array-HTA 2.0) from the plasma of 19 patients with castration-resistant prostate cancer at baseline and in patients after one cycle of cabazitaxel (C1). The patients were stratified in two groups (responders and nonresponders) according to their clinical response to cabazitaxel. Gene set enrichment analysis and ingenuity pathway analysis platforms were used for gene and pathway analysis. We detected molecular differences in the exosomes from two groups of patients (nonresponders vs. responders) at baseline in pathways related to prostate cancer, oncogenic signaling, cytoskeleton, and immune system. In nonresponders, we found enrichment of cytoskeleton related gene (Stathmin-1 and ITSN1) that have been associated with resistance to cabazitaxel. Monitoring of exosomal transcripts after the first cycle of treatment revealed changes in pathways associated with response to treatment. Sequential transcriptional profiling of plasma-derived exosomes reveals differential expression of genes that may reflect resistance to cabazitaxel treatment and therapy response.

Activity of lutetium-177 PSMA (Lu-PSMA) and determinants of outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with cabazitaxel: The PACAP study.

180 Background: Cabazitaxel and Lu-PSMA both improved survival in patients with mCRPC after docetaxel and an androgen receptor pathway inhibitor (ARPI), but there is limited data regarding Lu-PSMA activity after cabazitaxel. We aimed at assessing activity of Lu-PSMA and determinants of outcomes in this setting. Methods: Consecutive mCRPC patients from 6 European centers treated with Lu-PSMA after cabazitaxel were included in this retrospective study. Endpoints included radiographic progression-free survival (rPFS), time to PSA progression (PSA-TTP), PSA decline, objective response, overall survival, and safety. Results: Of 101 patients included (median age 67y), 64% had ISUP grade 4-5 disease; 71% had bone +/- nodal (LN) metastases, 22% visceral metastases, 7% LN only. All patients and 92% had received previous docetaxel and a prior ARPI (≥ 2 in 47%) before cabazitaxel respectively. Patients had received a median number of 6 cabazitaxel cycles (range 1-26). DNA damage repair alterations (DDR) were found in 11/48 (23%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (range 1-14). With a median follow-up of 5.7 months, the median rPFS from Lu-PSMA initiation was 4.3 months (m, 95%CI 3.2-5.7) and median PSA-TTP was 3.5 m (95%CI 3.0-4.5). Overall, 44 patients (44%) experienced a PSA decline ≥ 50% (PSA50), 54 (53%) ≥ 30% (PSA30), and 67 (66%) any PSA decline. Objective response rate was 34%. Baseline characteristics associated with shorter rPFS on Lu-PSMA included ISUP grade 4-5 disease (median rPFS of 3.5 vs. 7.2m, p=0.02) and a time to castration resistance < 12 months (3.1m vs. 4.5m, p=0.04). Patients with LN only had longer rPFS compared to those with bone and visceral metastases (median NR vs. 3.6 and 3.7m, respectively, p=0.02). There was no association between activity of Lu-PSMA and DNA damage repair alterations, duration of previous cabazitaxel therapy, and number of previous ARPI. During Lu-PSMA, a profound PSA decline was associated with longer rPFS: patients achieving PSA50, PSA30 or any PSA decline had respective median rPFS rates of 9.0, 8.3 and 6.2 months, while those who did not experience any PSA decline had a median rPFS of only 2.6 months. Conclusions: Lu-PSMA demonstrated substantial PSA decline but limited duration of response after cabazitaxel in a real-life setting. Adverse baseline characteristics and absence of PSA decline may help early identification of poor responders.

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.

Concept: A randomised multicentre trial of first line chemotherapy comparing three weekly cabazitaxel versus weekly paclitaxel in HER2 negative metastatic breast cancer

BackgroundPaclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer (MBC) patients. However, with response rates of 21.5–53.7% and significant risk of peripheral neuropathy, there is need for better chemotherapy. Patients and methodsThis open-label phase II/III trial randomised HER2-negative MBC patients 1:1 to either 6 cycles of three-weekly cabazitaxel (25 mg/m2), or, weekly paclitaxel (80 mg/m2) over 18 weeks.The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results158 patients were recruited. Comparing cabazitaxel to paclitaxel, median PFS was 6.7 vs 5.8 months (HR 0.87; 80%CI 0.70–1.08, P = 0.4). There was no difference in median OS (20.6 vs 18.2 months, HR 1.00; 95%CI 0.69–1.45, P = 0.99), ORR (41.8% vs 36.7%) or TTR (HR 1.09; 95%CI 0.68–1.75, P = 0.7).Grade ≥3 adverse events occurred in 41.8% on cabazitaxel and 46.8% on paclitaxel; the most common being neutropenia (16.5%) and febrile neutropenia (12.7%) cabazitaxel and neutropenia (8.9%) and lung infection (7.6%) paclitaxel. Peripheral neuropathy of any grade occurred in 54.5% paclitaxel vs 16.5% cabazitaxel.Mean EQ-5D-5L single index utility score (+0.05; 95%CI 0.004–0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1–12.3, P = 0.001) were higher in cabazitaxel vs paclitaxel. ConclusionsThree-weekly cabazitaxel in HER2-negative MBC does not significantly improve PFS compared to weekly paclitaxel, although it has a lower risk of peripheral neuropathy with better patient reported QoL outcomes. It is well tolerated and requires fewer hospital visits.

Activity of Cabazitaxel in Metastatic or Inoperable Locally Advanced Dedifferentiated Liposarcoma

Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. New drugs are required. To assess whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase 3 setting. This international multicenter, open-label single-arm phase 2 trial was conducted at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy. After mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. The primary end point was progression-free survival (PFS) rate at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression free at 12 weeks were needed. The final analysis report was completed on November 17, 2021. Forty patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Progression-free survival at 12 weeks was 55%, achieving the primary study end point. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate (RR) was 8% with 1 clinical response (CR) and 2 partial responses (PR). Twenty-three (60.5%) patients had a stable disease (SD). Disease control (PR+SD) was achieved in 26 patients (68%). This nonrandomized phase 2 clinical trial met its primary end point, with 21 of 38 patients (55%) being progression free at 12 weeks. These results suggest important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS. The drug is worth being further studied in these tumors in a phase 3 setting.

Comprehensive analysis of the associations between clinical factors and outcomes by machine learning, using post marketing surveillance data of cabazitaxel in patients with castration-resistant prostate cancer

BackgroundWe aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients.MethodsThe PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in ‘R’ package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS.ResultsAmong the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in ‘R’ package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan–Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS.ConclusionsNeutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

Cabazitaxel multiple rechallenges in metastatic castration-resistant prostate cancer.

IntroductionCabazitaxel multiple rechallenges may be a treatment option in heavily pretreated patients with metastatic castration‐resistant prostate cancer (mCRPC) who had a good initial response to cabazitaxel and who are still fit to receive it. Our objective was to assess the efficacy and toxicity of multiple rechallenges.Patients and methodsWe retrospectively identified 22 mCRPC patients previously treated with docetaxel and/or androgen receptor‐targeted agents who received multiple cabazitaxel rechallenges in 9 French centers. Cabazitaxel was initiated at a dose of 25 mg/m2 q3week. A reduced dose (20 mg/m2 q3w) or an alternative schedule (mainly 16 mg/m2 q2w) was increasingly used for subsequent rechallenges. Progression‐free survival, prostate‐specific antigen (PSA) response, best clinical response, and grade ≥3 toxicities were collected. Overall survival was calculated from various time points.ResultsTwenty‐two patients with an initial response to cabazitaxel were rechallenged at least twice. The median number of cabazitaxel cycles was 7 at first cabazitaxel treatment, 6 at first rechallenge, and 5 at subsequent rechallenges. Median progression‐free survival at first rechallenge was 9.6 months and 5.6 months at second rechallenge. Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. There was no cumulative grade ≥3 neuropathy or nail disorder and one case of febrile neutropenia.ConclusionCabazitaxel multiple rechallenges may be a treatment option without cumulative toxicity in heavily pretreated patients having a good response to first cabazitaxel use and still fit to receive it.Novelty & Impact StatementsPatients with metastatic castration‐resistant prostate cancer can be treated with Cabazitaxel after docetaxel and androgen receptor‐targeted agent. This chemotherapy can be used multiple times with efficacy and manageable toxicity.

Serum and hematologic responses after three cycles of cabazitaxel therapy as predictors of survival in castration-resistant prostate cancer.

In this study, we investigated the association between the early response of serum and hematological variables and the outcome of cabazitaxel therapy. The medical records of 59 consecutive patients who had previously received docetaxel chemotherapy for the treatment of metastatic castration-resistant prostate cancer (CRPC) and who received cabazitaxel at our hospital between January 2011 and March 2020 were retrospectively reviewed and statistically analyzed. The median follow-up period after cabazitaxel initiation was 15.2months. The 30% prostate-specific antigen (PSA) response rate, median PSA progression-free survival period, and overall survival (OS) period were 45.8%, 4.3months, and 22.6months, respectively. Within 1 to 2 cycles of cabazitaxel, we were unable to identify hematological or serum kinetics that had a relationship with OS. Analysis of the variables after 3 cycles of cabazitaxel, however, revealed two factors, PSA decline > 30% (p = 0.016) and neutrophil-lymphocyte ratio (NLR) decline > 30% (p = 0.044), as the predictors of favorable outcome for OS. We established a prognostic model for predicting the OS period composed of these two factors, which exhibited distinctly separated OS curves (p = 0.004). The C-index of a model incorporating these two factors was 0.703. This is the first study to demonstrate that PSA and NLR decline 3 cycles after the initiation of cabazitaxel were associated with favorable outcome in patients with CRPC. Also, 3 cycles of cabazitaxel might be necessary to assess the efficacy of cabazitaxel therapy.

Updated results of European Organization for Research and Treatment of Cancer (EORTC) phase 2 trial 1202 cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma.

11518 Background: Treatment options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited. The most effective agents include doxorubicin, ifosfamide, trabectedin and eribulin, but, in general, objective response rates (ORR) and progression free survival (PFS) are modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. The clinical cut-off date for the primary analysis was performed on August 31, 2020. Data base lock was performed on February 2, 2021. Eligible patients with metastatic or inoperable locally advanced DD LPS, after a centralized pathological review, were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Currently, a centralized radiological assessment is ongoing. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. One patient was still on treatment at the clinical cut-off date. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. PFS at 12 weeks was 55% (conditional 1-sided 95% CI 40.8-100), achieving the primary study endpoint. The median FU was 21.6 months, median PFS was 6 months and median OS 21 months. RR was 8% with one CR and two PR. Twenty-three(60.5%) pts had a SD. Disease control (PR+SD) was achieved in 26 patients (68%). The most common cabazitaxel -related grade >3 adverse events in all 40 registered patients were Neutrophil count decreased (50%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 21/38 pts (55%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and looks interesting if compared to the other available options and experimental drugs recently reported in this patient population. Clinical trial information: NCT01913652.

Randomized multicenter trial of 3 weekly cabazitaxel versus weekly paclitaxel chemotherapy in the first-line treatment of HER2 negative metastatic breast cancer (MBC).

1008 Background: Paclitaxel is commonly used as first line chemotherapy for HER2 negative MBC. However, with response rates of 21.5-53.7% and a significant risk of peripheral neuropathy there is a need for more effective and better tolerated chemotherapy (CCT). Methods: This open label randomised (1:1) phase 2 trial compared 6 cycles of cabazitaxel (25 mg/m2) every 3 weeks, with weekly paclitaxel (80mg/m2) over 18 weeks as first line CCT. HER2 negative and performance status ≤1 patients were eligible. Patients on cabazitaxel received GCSF prophylaxis. Primary endpoint was Progression Free Survival (PFS) with 127 events required to detect a hazard ratio (HR) of 0.65 with 85% power. Secondary endpoints included objective response rate (ORR; RECIST 1.1), time to response (TTR), overall survival (OS), safety and tolerability and quality of life (QoL). Results: 158 patients were recruited from 14 UK hospitals (79 in each arm). Median age (range) was 56(34-81) in the cabazitaxel arm and 61(34-79) in the paclitaxel arm. 61% of patients were performance status 0. Median time on treatment was 15 weeks for both arms, but more patients on paclitaxel had a treatment delay (61% vs 39%) or dose reduction (37% vs 24%). Comparing cabazitaxel to paclitaxel after 146 PFS events, median PFS was 6.7 vs 5.8 months (HR 0.84; 95%CI 0.60–1.18, P = 0.3). There was no difference in OS, median 19.3 vs 20.0 months (HR 0.94; 95%CI 0.63-1.40, P = 0.7), ORR (42% vs 37%) or TTR (HR 1.09; 95%CI 0.68–1.74, P = 0.7). Grade ≥3 adverse events occurred in 42% of patients on cabazitaxel and 48% on paclitaxel. Diarrhoea, febrile neutropenia and nausea were the most common grade ≥3 events in the cabazitaxel arm with rates of 11%, 11% and 10% respectively compared to 1%, 1% and 0% in the paclitaxel arm. In the paclitaxel arm the top grade ≥3 events were lung infection and peripheral neuropathy, 6% and 5% respectively compared to 2.5% and 0% in the cabazitaxel arm. Peripheral neuropathy of any grade was reported by 55% of patients treated with paclitaxel vs 17% on cabazitaxel. Alopecia occurred in 41% of patients on paclitaxel compared to 27% on cabazitaxel. Adverse events leading to discontinuation were more frequent with paclitaxel (22%) than cabazitaxel (14%). Over the course of treatment, mean EQ5D single index utility score (+0.05; 95%CI 0.004-0.09, P = 0.03) and visual analogue scale score (+7.7; 95%CI 3.1-12.3, P = 0.001) were higher in the cabazitaxel arm compared to paclitaxel suggestive of better QoL on Cabazitaxel. Conclusions: 3 weekly cabazitaxel as first line chemotherapy in HER2 negative MBC does not significantly improve PFS compared to weekly paclitaxel, though it has a lower risk of peripheral neuropathy with better patient reported overall health outcomes. Cabazitaxel is safe and well tolerated for MBC and requires fewer hospital visits, an important consideration in the COVID pandemic and beyond. Clinical trial information: NCT03048942 .

Cabazitaxel multiple rechallenge in metastatic castration-resistant prostate cancer: A therapeutic option to increase overall survival?

97 Background: Cabazitaxel rechallenge could be a more efficient therapy with an acceptable toxicity than docetaxel in the treatment of patients with a metastatic castration resistant prostate cancer (mCRPC). The aim of this study was to assess the feasibility and efficacy of cabazitaxel multiple rechallenge. Methods: This is a multicenter, retrospective cohort study including patients from 9 centers in France who received 3 lines or more of cabazitaxel from February 2012 to July 2020. Cabazitaxel schedule differed between patients: 25 mg/m2 q3w, 20 mg/m2 q3w, 16 mg/m2 q2w or 10 mg/m2 weekly. Efficacy was assessed by overall survival (OS) and progression-free survival (PFS) from each cabazitaxel line start. Only toxicities grade ≥ 3 were reported. Results: Twenty-two patients were included. The median follow-up from mCRPC was 94.7 months, median age at initial diagnosis was 59.5 years old, median ISUP score at diagnosis was 4 and median PSA at diagnosis was 55 ng/ml. Median number of cabazitaxel cycles was 7 at first-line, 6 at first rechallenge, and 5 for subsequent rechallenges. Median OS from mCRPC diagnosis was 105 months. Median PFS from cabazitaxel line start was 11.8 months at first use, 9.6 for first rechallenge and 5.6 in second rechallenge (table). Only one case of febrile neutropenia and 6 events of grade ≥ 3 toxicity were reported. Conclusions: Cabazitaxel multiple rechallenge could efficiently extend OS with manageable toxicities for patients. Even if anti-PARP therapy and immunotherapy are promising treatments, cabazitaxel rechallenge could be also a relevant therapeutic option for long responder patients. Specific biomarkers should be explored to predict the efficacy of cabazitaxel rechallenge. [Table: see text]

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.

Activity of cabazitaxel in patients with metastatic or inoperable locally advanced dedifferentiated liposarcoma: European Organization for Research and Treatment of Cancer (EORTC) Phase II trial 1202.

11556 Background: The optimal treatment for patients with advanced dedifferentiated (DD) liposarcoma (LPS) remains uncertain. Single agents which are most effective include doxorubicin and ifosfamide but, as with soft tissue sarcomas (STS) in general, objective response rates (ORR) and progression free survival (PFS) are very modest. Cabazitaxel exerts its effect through inhibition of microtubular disassembly and has been shown to be relatively safe, effective and well-tolerated. EORTC 1202 assessed whether cabazitaxel demonstrated sufficient antitumor activity in patients with metastatic or inoperable locally advanced DD LPS to justify further investigation in a phase III setting. Methods: This was an international multi-center, open label single arm phase II trial. Eligible patients with metastatic or inoperable locally advanced DD LPS were treated with cabazitaxel 25mg/m² IV infusion over 1 hour every 21 days. Primary endpoint was PFS rate at 12 weeks assessed by local investigator per RECIST 1.1. Based on a Simon two-stage design, at least 4 out of 17 (Stage 1) and 11 out of 37 (Stage 2) eligible and evaluable patients who are progression-free at 12 weeks were needed. Results: Forty patients were registered by 10 institutions in 4 countries between March 2015 and March 2019, with 2 patients being ineligible. Among the 38 eligible patients who started treatment, 3 (7.5 %) were still on treatment at the time of analysis. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65%) received at least 4 cycles of cabazitaxel. Among the first 17 (Stage 1) and 37 (Stage 2), 11 and 20 patients were progression-free at 12 weeks respectively, satisfying the study decision rules. The PFS rate at 12 weeks for all 38 eligible patients was 52.6% (conditional 1-sided 95 % CI 38.3 – 100). Two patients (5.3%) achieved a confirmed partial response (PR) and 23 stable disease (SD) (60.5%). Disease control (PR+SD) was achieved in 25 patients (65.8%). Median PFS was 7.4 months (95%CI 2.8-10.3). The most common cabazitaxel -related grade &gt;3 adverse events in all 40 registered patients were neutropenia (60%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were no cabazitaxel-related deaths. Conclusions: EORTC 1202 met its primary endpoint, with 20/37 pts (54%) being progression-free at 12 weeks. Results of this trial confirm activity of cabazitaxel in patients with metastatic or inoperable locally advanced DD LPS and warrant further exploration of the drug. Clinical trial information: NCT01913652 .

Effect of Baseline Characteristics on Cabazitaxel Treatment Duration in Patients with Metastatic Castration-Resistant Prostate Cancer: A Post Hoc Analysis of the Compassionate Use/Expanded Access Programs and CAPRISTANA Registry.

We examined factors that may impact cabazitaxel treatment duration in a real-life setting in a compassionate use program, expanded access program, and prospective observational study in metastatic castration-resistant prostate cancer (mCRPC). Patients with mCRPC previously treated with docetaxel (N = 1621) received cabazitaxel 25 mg/m2 intravenously every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. The median number of cabazitaxel cycles was six (range, 1–49); 708 patients (43.7%) received >6 cycles. Patients receiving >6 cycles tended to have a better Eastern Cooperative Oncology Group performance status of 0–1 (p = 0.0017 for ≤6 vs. >6 cycles). Overall, 348 patients (21.5%) were ≥75 years of age; 139 (39.9%) received >6 cycles. The main reason for discontinuation was disease progression; however, in patients receiving 1–2 cycles, the main reason for discontinuation was adverse events. Only 52 patients (3.2%) progressed during cycles 1–2. Cabazitaxel was well tolerated in these studies, which included some elderly and frail patients, offering clinicians an important treatment option in the management of mCRPC. Proactive management of adverse events may allow patients to receive a higher number of cabazitaxel cycles and derive greater benefit.

Efficacy of cabazitaxel second-line and beyond.

226 Background: Prostate cancer accounts for the 2nd most common cause of cancer deaths in males in the UK. Cabazitaxel (CBZ) is a third generation taxane with activity demonstrated even in docetaxel resistant cases. Results of the TROPIC study established survival benefit for CBZ in metastatic castrate resistant prostate cancer (mCRPC) patients but there was also a higher incidence of febrile neutropenia (FN) reported. We studied the efficacy of CBZ in mCRPC patients treated in our centre and assessed FN rates with the use primary granulocyte colony stimulating factor (GCSF) support. Methods: We conducted a retrospective audit of mCRPC patients treated with CBZ from January 2016 – January 2019. We analysed treatment outcomes, FN rates and potential prognostic factors. Results: There were 42 patients in total with a median age of 70 years (range; 54-91). The median follow up was 9.5 months (range; 2-34 months). Most of our patients had extensive disease, with bone and visceral metastases seen in 88% and 31% respectively. CBZ was given as second line treatment in 15 (35.7%) patients on progression following docetaxel and as third line in 27 (64.3%) patients. Majority of our patients (95%) had WHO PS of either 0 or 1. Median number of cycles of CBZ administered was 6 and 31% of patients completed 10 cycles of treatment. Median biochemical progression free survival (PFS) for patients who received at least 3 or more cycles of CBZ was 6 months and median overall survival (OS) was 11 months. Median OS for patients who received CBZ as 2nd line and 3rd line treatments were 9 and 13 months respectively. Patients with visceral metastases had a median OS of 9 months. Median OS for patients with Haemoglobin (Hb) ≥12gm/dl and lower Hb were 19 and 9 months respectively (p = 0.004). Patients in favourable prognostic group (Normal Hb, Normal albumin and no visceral metastases) had a median OS of 24 months compared to 10 months for those in less favourable group. There were no episodes of FN reported in our group with the use of primary GCSF prophylaxis. Conclusions: CBZ is effective as a 2nd or 3rd line treatment option in patients with mCRPC. Neutropenic complications can be significantly reduced with the use of primary GCSF prophylaxis. Low pre-treatment Hb seems to be a predictor for poor overall survival.