The results of the CABASTY phase III randomised study demonstrate that a biweekly schedule of cabazitaxel 16 mg/m2 plus prophylactic granulocyte colony–stimulating factor (G-CSF) at every cycle, significantly reduce the risk of severe neutropenia and/or neutropenic complications compared with the standard regimen of triweekly cabazitaxel 25 mg/m2 plus G-CSF in patients 65 years or older with metastatic castration-resistant prostate cancer (mCRPC) who had not responded to previous docetaxel and androgen receptor (AR)-targeted agents.

Furthermore, in this older and heavily pretreated population, median overall survival (OS) reached 14.1 months in both groups. There was no significant difference between groups in radiographic progression-free survival, PSA response, objective tumour response, and time to skeletal-related events. The findings are published by Dr. Stéphane Oudard of the Department of Medical Oncology, Georges Pompidou Hospital in Paris, France, and colleagues on 26 October 2023 in the JAMA Oncology.

Despite level 1 evidence for cross-resistance, many patients with mCRPC, especially those 65 years or older, receive AR-targeted therapies in sequence before receiving chemotherapy, possibly because of concerns about the side effects of chemotherapy. In patients 75 years and older, standard regimens of taxanes are commonly associated with more grade 3 or higher adverse events and treatment discontinuations due to adverse events than in younger patients, despite providing a survival advantage in older patients and substantial reduction of pain, which is important at such an advanced stage of the disease.

Patients receiving cabazitaxel experience less alopecia, peripheral neuropathy, peripheral oedema, and nail disorders than those receiving docetaxel, but cabazitaxel is associated with a high rate of grade 3 or higher neutropenia. Although the risk of neutropenic complications can be partly mitigated by a lower cabazitaxel dose, and/or prophylactic G-CSF from cycle 1, this risk remains a challenge in patients 65 years or older with mCRPC associated with comorbidities and/or age-related decline in organ function, polypharmacy, and risk of potentially serious drug-drug interactions. To further reduce the incidence of severe neutropenia and its complications, an alternative strategy is to change the schedule of administration.

The CABASTY phase III randomised study was designed to test the hypothesis that cabazitaxel 16 mg/m2 plus G-CSF administered every 2 weeks is associated with a lower incidence of grade 3 or higher neutropenia and/or neutropenic complications compared with the standard cabazitaxel regimen of 25 mg/m2 plus G-CSF administered every 3 weeks in patients 65 years or older with mCRPC who had not responded to previous docetaxel and AR-targeted agents.

A total of 196 patients 65 years or older with progressive mCRPC were enroled in this prospective phase III randomised study conducted in 18 centres in France and 7 centres in Germany between 5 May 2017 and 7 January 2021. All patients had received docetaxel and at least 1 novel AR–targeted agent. Patients were randomly assigned 1:1 to receive biweekly cabazitaxel 16 mg/m2 plus G-CSF and daily prednisolone (99 patients, experimental group) or triweekly cabazitaxel 25 mg/m2 plus G-CSF and daily prednisolone (97 patients, control group). The primary endpoint was the occurrence of grade 3 or higher neutropenia measured at nadir and/or neutropenic complications.

Among 196 patients, the median (IQR) age was 74.6 (70.4-79.3) years, and 181 (92.3%) had an ECOG performance status of 0 or 1. The median (IQR) follow-up duration was 31.3 (22.5-37.5) months. Relative dose intensities were comparable between groups. The rate of grade 3 or higher neutropenia and/or neutropenic complications was significantly higher with triweekly cabazitaxel 25 mg/m2 versus biweekly cabazitaxel 16 mg/m2 (62.5% versus 5.1%, odds ratio 0.03; 95% confidence interval 0.01-0.08; p < 0.001).

Grade 3 or higher adverse events were more common with triweekly cabazitaxel 25 mg/m2 (72.9%) versus biweekly cabazitaxel 16 mg/m2 (56.1%). No patient developed febrile neutropenia with the biweekly regimen compared with 10.4% of patients with the standard regimen. One patient in triweekly cabazitaxel 25 mg/m2 group died of a neutropenic complication.

Because the risk of grade 3 or higher neutropenia increased with age and is already high in patients younger than 75 years, these data may be practice changing, especially in patients 65 years or older with mCRPC who are often denied chemotherapy in daily clinical routines.

This study was funded by Sanofi. Sanofi also provided cabazitaxel and G-CSF for the study.

Reference

Oudard S, Ratta R, Voog E, et al. Biweekly vs Triweekly Cabazitaxel in Older Patients With Metastatic Castration-Resistant Prostate Cancer The CABASTY Phase 3 Randomized Clinical Trial. JAMA Oncol. Published online 26 October 2023. doi:10.1001/jamaoncol.2023.4255

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