Cabazitaxel Treatment Research Articles

Renal Failure and Hypocalcaemia Secondary to Cabazitaxel Treatment for Prostate Cancer: A Rare but Potentially Lethal Side Effect

Farrouq Mahmood1*, Mazan Matar2 and Andrew Davis3 1Specialty Doctor in Oncology at North Devon District Hospital, Barnstaple, UK 2Core Medical Trainee at North Devon District Hospital, Barnstaple, UK 3Consultant in Gastroenterology at North Devon District Hospital, Barnstaple, UK *Corresponding author: Farrouq Mahmood, Specialist Doctor in Oncology, North Devon District Hospital, UK, Tel: 07825290631; E-mail: farrouqmahmood@doctors.org.uk

Activity of Cabazitaxel in Castration-resistant Prostate Cancer Progressing After Docetaxel and Next-generation Endocrine Agents

BackgroundCabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians. ObjectiveTo describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents. Design, setting, and participantsWe report on a cohort of 59 men with progressing CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of whom had received prior enzalutamide. Outcome measurements and statistical analysisChanges in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy. Results and limitationsThe post–endocrine-therapy patients received abiraterone (n=32), sequential abiraterone and enzalutamide (n=5) or enzalutamide (n=4). These patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median of six cabazitaxel cycles (range: 1–10 cycles) were delivered, with ≥50% PSA declines in 16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naïve cohort (n=18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis. ConclusionsThis is the first report of cabazitaxel activity in CRPC progressing after treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant cabazitaxel activity in this setting. Patient summaryWe looked at the antitumour activity of the chemotherapy drug cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after these novel endocrine treatments.

Genistein enhances the efficacy of cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer cells.

Cabazitaxel (Jevtana) has been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, most patients progress and become chemoresistant, which remains a major challenge in the management of advanced PCa. In this study, we investigated whether genistein, an isoflavone abundant in soy products, could sensitize mCRPC cells to cabazitaxel treatment in experimental models. The in vitro and in vivo effect of genistein in enhancing the response of mCRPC cells to cabazitaxel chemotherapy was evaluated in experimental models. Genistein increases the expression of pro-apoptotic protein Bax, activates apoptotic signals, and enhances the response to cabazitaxel treatment in mCRPC cells. In a PC3-luciferase xenograft model, the combined treatment with genistein and cabazitaxel significantly retarded the growth of mCRPC when compared to vehicle control, cabazitaxel, or genistein. Tissue staining confirmed the in vivo effect of genistein on the induction of Bax and activation of apoptosis. This study provided the first preclinical evidence supporting that genistein could be beneficial in improving cabazitaxel chemotherapy in mCRPC.

Quality of life (QoL) of patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel.

e16088 Background: The effects of cabazitaxel on QoL, pain response and preference/utility data have not been well studied in men with CRPC treated post-docetaxel. As part of a single-arm multicenter Sanofi-funded Early Access Program (EAP) for cabazitaxel, QoL data were collected on Canadian patients. Methods: Between May 2011 and February 2012, 61 patients (pts) were enrolled at 9 centers. QoL was assessed at the start of each cycle using the FACT-P and its subscales, and the EQ 5D-3L. EQ 5D-3L health state index (HIS) data were converted into utility values (Canadian tariff, Bansback 2011). Present pain intensity (PPI) and analgesic scores were assessed using the McGill-Melzack questionnaire. Results: QoL data were evaluable in 55 pts. Baseline pt characteristics were: median age 65 years (range, 42-79), 92.7% of pts were ECOG PS 0 or 1, 87% had bone metastases, and 56% (31/55) received at least 6 cycles of cabazitaxel. Statistically significant changes from baseline in mean QoL scores were observed on FACT-P total score at cycle 2, and prostate cancer specific subscale (PCS) at cycles 1 to 4. As a measure of QoL response, increases were observed and maintained for > 2 consecutive cycles in 9% (>16 points) and 25% (≥10) of pts for FACT-P total score. Improvements to the level of Minimal Important Differences (MID) (Cella 2009) maintained for > 2 consecutive cycles were observed in 36% of pts for FACT-P total score (MID=6), 49% for PCS subscale (MID=2), and 26% for PCS-Pain subscale (MID=2), respectively. The percentage of pts reporting "no problem" in the EQ-5D pain/discomfort domain were above baseline levels at every cycle and improved from baseline to end of treatment from 19% to 29% (p < 0.05). Other EQ-5D dimensions (anxiety/depression, mobility, self-care and usual activities) remained stable over the course of treatment. Improvement from baseline in utility value (HIS) was observed at cycle 4 with a utility value of 0.769 (vs 0.713 at baseline). PPI scores improved despite stable analgesic use and were significantly different from baseline at cycles 2, 4 and 9. Conclusions: Data from this EAP suggest improvements in QoL, pain and prostate cancer specific symptoms with second-line cabazitaxel treatment. Clinical trial information: NCT01254279.

Cabazitaxel in Patients With Metastatic Castration-Resistant Prostate Cancer: Results of a Compassionate Use Program in The Netherlands

BackgroundCabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of the Dutch CUP, detailing the safety and efficacy of cabazitaxel in a routine clinical practice setting. Patients and MethodsSafety and efficacy data of all 5 Dutch centers participating in the cabazitaxel CUP were collected. Safety data were collected prospectively using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. Overall survival (OS) and progression-free survival (PFS), time to PSA progression (TTPP), and best clinical response were evaluated retrospectively. ResultsFifty-one patients were registered in the CUP; 49 received cabazitaxel. Forty-two of 49 patients [85.7%], 42 patients had ≥ 2 metastatic sites. Patients received on average 6 cabazitaxel cycles (range, 1-21). A dose reduction or dose delay occurred in 13 and 20 patients [26.5% and 40.9%] respectively. Prophylactic granulocyte colony-stimulating factor (G-CSF) was used in 8 patients [16.3%]. Grade ≥ 3 adverse events were observed in 25 patients [51.0%]; 16 patients [32.7%] discontinued treatment because of treatment-emergent adverse events (TEAEs). Serious adverse events (SAEs) occurred in 16 (32.7%) patients; the most frequent SAEs were hematuria (4 patients [8.3%]) and urosepsis (3 patients [6.3%]). Febrile neutropenia occurred twice; no patient had grade ≥ 3 neuropathy. No toxicity-related mortality occurred. Median follow-up was 24.1 months. Median OS was 8.7 months (interquartile range [IQR], 6.0-15.9 months); median TTPP was 2.8 months (IQR, 1.7-5.9 months). ConclusionIn the Dutch CUP, patients with advanced mCRPC had delayed tumor progression with acceptable toxicities using cabazitaxel treatment.

Abstract 316: Cabazitaxel antitumor activity in docetaxel-resistant patient-derived prostate cancer xenograft models.

Abstract Introduction: The first line of chemotherapy for castration resistant prostate cancer (CRPC) patients is docetaxel treatment. Continued treatment after progression on docetaxel with cabazitaxel can be very strenuous for patients. Clearly, selection of patients that will benefit from either docetaxel or cabazitaxel treatment would be an essential asset to the management of CRPC. Therefore docetaxel-resistant, CRPC xenografts PC339-DOC and PC346C-DOC were developed. These xenografts were tested for sensitivity to cabazitaxel as an initial step to develop a biomarker gene expression profile of docetaxel resistance and cabazitaxel sensitivity in CRPC. Materials and Methods: PC339 (low sensitivity to docetaxel, log cell kill 0.7) and PC346C (moderate sensitivity to docetaxel, log cell kill 1.0) bearing mice were treated with bolus injections of docetaxel (33 mg/kg) every two weeks until the tumor became resistant. Cabazitaxel efficacy was tested in the resistant xenografts by treating PC339-DOC and PC346C-DOC bearing mice with a single bolus injection cabazitaxel (33 mg/kg). Body weight and tumor volume (TV) were monitored up to 160 days post-treatment. Log cell kill was calculated as measure of antitumor activity, taken into account the tumor growth delay induced by the treatment and the tumor doubling time of the tumor (log cell kill= tumor growth delay / tumor doubling time x 3,32). Log cell kill values of < 0.7 reflect no antitumor activity. Importantly, both naïve and resistant xenografts are lacking expression of docetaxel transporter P-glycoprotein (P-gp/ABCB1/MDR1). Results: PC339-DOC was generated within 4 months after start of docetaxel treatment suggesting some intrinsic resistance against docetaxel. In contrast, PC346C-DOC could be classified as acquired resistance as it took more than one year to develop docetaxel resistance in the naïve PC346C. Cabazitaxel was highly active in PC339-DOC, causing complete regression in 4 out of 5 mice (log cell kill > 2.8) while cabazitaxel lacked antitumor activity in PC346C-DOC (log cell kill 0.20). Conclusion: Cabazitaxel was highly active in a docetaxel-resistant PC339DOC xenograft. Low antitumor activity in PC346C-DOC suggests different mechanisms of resistance in both resistant models and potential cross-resistance between taxanes. The differences between PC339-DOC and PC346C-DOC will allow the development of a biomarker profile to specifically select CRPC patients that could benefit from continued treatment with taxanes. Citation Format: Ellen S. de Morree, Corrina M.A. de Ridder, Herman Burger, Erik A.C. Wiemer, Ron H.J. Mathijssen, Ronald de Wit, Wytske M. van Weerden. Cabazitaxel antitumor activity in docetaxel-resistant patient-derived prostate cancer xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2013-316

Cabazitaxel for prostate cancer: patient preparation and ongoing care

Cabazitaxel, a new-generation taxane that fulfils a hitherto unmet need for second-line chemotherapy in metastatic castrate-resistant prostate cancer, has received approval from the European Medicines Agency. In a recent phase III clinical trial, this drug showed a survival benefit over mitoxantrone; however, it was associated with significant side effects, most notably neutropenia, diarrhoea, nausea/vomiting, peripheral neuropathy and fatigue. Careful patient selection for cabazitaxel is essential, as is a robust management plan for the detection, assessment and prompt treatment of any side effects. This article examines the nurse's role in patient preparation, education, ongoing monitoring and support throughout cabazitaxel treatment.

Cabazitaxel for prostate cancer: patient preparation and ongoing care

Cabazitaxel, a new-generation taxane that fulfils a hitherto unmet need for second-line chemotherapy in metastatic castrate-resistant prostate cancer, has received approval from the European Medicines Agency. In a recent phase III clinical trial, this drug showed a survival benefit over mitoxantrone; however, it was associated with significant side effects, most notably neutropenia, diarrhoea, nausea/ vomiting, peripheral neuropathy and fatigue. Careful patient selection for cabazitaxel is essential, as is a robust management plan for the detection, assessment and prompt treatment of any side effects. This article examines the nurse's role in patient preparation, education, ongoing monitoring and support throughout cabazitaxel treatment.

Abstract 2775: Antitumor activity of cabazitaxel in pediatric tumor xenografts

Abstract Background: Cabazitaxel (Jevtana®), a novel semi-synthetic taxane derived from 10-deacetyl baccatin III, was recently approved by the FDA and EMA for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy. Cabazitaxel, which stabilizes in vitro microtubules as efficiently as docetaxel, was selected for clinical development for several reasons including: better anti-proliferative activity than docetaxel against chemotherapy resistant tumor cell lines (Bissery MC, AACR 2000), broad spectrum of in vivo anti-tumor activity docetaxel-sensitive tumors, and activity in tumor models in which docetaxel was either poorly active or inactive (Vrignaud P, AACR 2000). Interestingly, unlike docetaxel, cabazitaxel is able to cross the blood-brian barrier (Dykes DJ, AACR 2000) and has demonstrated activity in intracranial human glioblastomas. Further, in preclinical studies the combination of cabazitaxel and cisplatin exhibit therapeutic synergism (Vrignaud P, AACR 2011). Methods: In order to explore other therapeutic indications, the anti-tumor activity of cabazitaxel was evaluated in comparison to docetaxel in 3 different xenograft models of human pediatric tumors: RH-30 (rhabdomyosarcoma), TC-71 and SK-ES-1 (Ewing's tumors) in SCID female mice. Cabazitaxel and docetaxel were administered as single agents, IV in a dose response study (14.5, 9.0, 5.6 & 3.5 mg/kg), 5 days apart (e.g., days 14 and 18) after SC tumor implantation. Results: In the rhabdomysarcoma RH-30 model, cabazitaxel achieved 100% complete regression (CR) at the 2 highest dose levels and tumor regressions were also observed at the third dose level. Tumor free survivors (TFS on day 120) were observed only in the cabazitaxel treatment groups, 14.5 mg/kg (6/6) and at 9 mg/kg (5/6). In comparison, docetaxel induced CR only at the highest dose-level (14.5 mg/kg) tested. Against TC-71, cabazitaxel achieved 6/7 TFS at14.5 mg/kg and 9 mg/kg and 6/7 partial regressions (PR) were observed at 5.6 mg/kg. However, docetaxel only induced CR at the highest dose-level tested (14.5 mg/kg) with 1/7 TFS at day 120. Against SK-ES-1, cabazitaxel achieved 100% PR at 14.5, 9.0, 5.6 mg/kg, with 6/7 CR, leading to 3/7 TFS at the highest doses tested. In comparison, docetaxel induced 3/7 CR at the highest dose tested and no TFS were observed. Conclusion: Both cabazitaxel and docetaxel showed significant antitumor activity in all 3 human pediatric tumor xenografts; however, cabazitaxel demonstrated greater activity than docetaxel at comparable dose levels. Taken together, preclinical data with cabazitaxel including activity in brain tumors and therapeutic synergism with cisplatin, support its development in pediatric indications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2775. doi:1538-7445.AM2012-2775

Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): Interim safety and quality-of-life (QOL) data from the U.K. early access program (NCT01254279).

44 Background: Cabazitaxel, a tubulin-binding taxane, improved survival in mCRPC in the TROPIC trial. Notable toxicities were neutropenia and diarrhoea. We report interim safety and QOL data from a single arm multicentre open label study providing early access to cabazitaxel in the UK. Methods: Patients recruited from 12 centres received cabazitaxel 25mg/m2 intravenously every 3 weeks and prednisolone 10mg daily. Safety assessments were performed before each cycle. Patients completed the EQ-5D questionnaire and health state visual analogue scale (VAS) at baseline and at alternate cycles. Patients recruited before March 31st 2011 are included in the safety analysis. QOL data collected before July 31st 2011 at baseline (n=62), cycle 2 (n=50) and cycle 4 (n=26) are included. Results: Median age was 68 years; 24% were aged over 75 years. 93% had bone metastases. 50% had experienced disease progression during or within 3 months of docetaxel and the remaining 50% within 3-6 months. A median of 3 cycles of cabazitaxel were completed with 99% relative dose intensity. 83% continued cabazitaxel at the time of safety analysis. 7 patients stopped before completing the full course, 5 of these were due to disease progression. One treatment related death occurred within 30 days of the last cabazitaxel infusion (2.4%). 85% of patients received granulocyte-colony stimulating factor prophylaxis from cycle 1. The proportion of patients reporting no pain or discomfort increased between baseline, cycle 2 and cycle 4 (22.6% to 38% to 50%). Anxiety and depression, mobility and self-care scores from EQ-5D were stable. Median VAS health state increased from baseline (75%) to cycle 4 (79%). Conclusions: Improvements in pain control and health states were reported during early stages of cabazitaxel treatment. Other EQ-5D QOL measures were stable. Severe toxicity was rare. Results will be updated from final analysis in late 2011. [Table: see text]