Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone

Abstract

BackgroundAbiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536).Patients and methodsThe primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II).ResultsTen patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1–28). Grade 3–4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6–66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1–10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors.ConclusionsThe combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

Phenotypes of circulating tumour cells predict time to castration resistance in metastatic castration‐sensitive prostate cancer

“…Androgen deprivation therapy (ADT) is the cornerstone of treatment for metastatic prostate cancer . Although most patients exhibit an initial response to ADT, most rapidly progress to castration‐resistant prostate cancer (CRPC) . With the deterioration of a patient's overall health and worsening symptoms, metastatic CRPC is invariably fatal .…”

Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug–Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients

“…In a recent study by Massard and colleagues on the combination of cabazitaxel and abiraterone, also a lower incidence of grade !3 neutropenia was reported than in the TROPIC trial (56%). This lower incidence of neutropenia did not result in less (marker) efficacy, as PSA levels dropped in 46% patients (4).…”

“…Clinical studies with various combinations of therapies, for example, taxanes with novel hormonal therapies, with various designs and aims, are in progress (e.g., https:// clinicaltrials.gov/ct2/show/NCT02522715; refs. [2][3][4][5]. A summary of ongoing clinical trials on these combinations was recently reviewed by Sternberg, and showed the rationale for combination therapies (6).…”

Cabazitaxel in the treatment of castration-resistant cancer: hitting the balance of efficacy and safety

“…Результаты КИ I/II фазы по применению комбинации кабазитаксела (25 мг/м 2 1 раз в 3 недели) с абиратероном (1000 мг/сут) после доцетаксела обнадеживают: частота ПСА-ответа достигла 46,2%, что выше, чем в регистрационных исследованиях кабазитаксела (39%) и абиратерона (29%). Профиль безопасности комбинации приемлемый [33]. Продолжается изучение кабазитаксела в комбинации с ИАС абиратероном и энзалутамидом.…”