ASCO 2019: Updated Results from a Randomized Phase II Study of Cabazitaxel versus Abiraterone or Enzalutamide in Poor Prognosis Metastatic CRPC - Medical Oncologist Perspective

Chicago, IL ( For patients with metastatic castration-resistant prostate cancer (mCRPC), there are currently six FDA approved therapies: docetaxel, cabazitaxel, enzalutamide, abiraterone, sipuleucel-T, and radium 223. Sipuleucel-T works best for patients who have asymptomatic mCRPC and radium 223 is used for patients with bone-only disease. For the other therapies, we currently lack randomized data to help decide the optimal sequencing of these life-prolonging agents. Retrospective data has previously described the survival of patients treated with abiraterone, enzalutamide, and cabazitaxel, but cross-trial comparisons are not possible, given that the groups were not balanced with respect to risk factors such as visceral disease. Kim Chi, MD, reports the updated data regarding a randomized phase II trial of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis mCRPC.
This abstract reports on data from 95 patients who were randomized to receive cabazitaxel first (arm A) or either enzalutamide or abiraterone (arm B). The study was planned for 120 patients but there was poor accrual so it was closed after 95 patients. This was a population of patients with many high-risk characteristics including liver metastases, CRPC in under 12 months from ADT initiation, and four or more poor prognostic criteria (high LDH, poor ECOG performance status, low albumin, high alkaline phosphatase, etc.).2 52% of patients had prior docetaxel chemotherapy. At the time of progression, the patients would cross over to the other arm. The primary objective of this study was to evaluate the clinical benefit rate, as defined by a PSA decline ≥50% (PSA50), objective response (OR), or stable disease (SD) ≥ 12 weeks. Prospective biomarker collection was performed to analyze serial circulating tumor DNA (ctDNA). 

Results showed that patients receiving cabazitaxel had a greater clinical benefit rate than those patients who received second-generation androgen antagonists (abiraterone or enzalutamide), 88% vs 70%, p=0.043. However, there was no significant difference between PSA50 (61% vs 62%), objective response rates (23% vs 17%), or median progression-free survival (PFS) (5.8 months vs 3.1 months). Median overall survival (OS) for those receiving cabazitaxel first was 37 months, compared with 15.5 months for patients receiving abiraterone or enzalutamide. However, this did not reach statistical significance (HR 0.57 (95%CI 0.31-1.03), p=0.06).

In terms of the correlative studies, ctDNA alterations were frequently observed in the AR, TP53, PI3K pathway, RB1, and DNA repair pathways. Patients with AR gain and TP53 alterations had shorter PFS and OS, and the combination of TP53 and RB1 alterations was worse than TP53 defects alone. ctDNA data was very compelling as a prognostic indicator. No patients with undetectable ctDNA have died thus far in the study.

For patients with mCRPC and poor prognostic factors, starting with cabazitaxel therapy over abiraterone or enzalutamide is a reasonable approach and may increase the clinical benefit rate in patients. There is a signal towards increased overall survival with this approach as well (37 months vs 15.5 months) although this did not reach statistical significance. This approach, of course, assumes that your patient is a candidate for chemotherapy and applies to patients who have been pre-treated with docetaxel chemotherapy in the metastatic castration sensitive setting. In terms of the correlative studies, ctDNA was extremely prognostic. While this fact isn’t surprising on its own, it may be useful to stratify future clinical trials based on ctDNA to help balance treatment/control arms. ctDNA should be studied as a surrogate endpoint in future prospective clinical trials. 

Presented by: Kim N. Chi, MD, FRCPC, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

Written by: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu, at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

  1. Climent Duran MA, Sáez MI, Piulats JM, et al. Treatment efficacy of abiraterone (abi), enzalutamide (enza) or cabazitaxel (caba) in metastasic castration-resistant prostate cancer patients (mCRPC) after progression to docetaxel plus androgen deprivation therapy (ADT) in hormone sensible disease. American Society of Clinical Oncology; 2019.
  2. Chi K, Kheoh T, Ryan C, et al. A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel. Annals of Oncology 2015;27:454-60.