ASCO 2019: A Multicentric Phase II Randomized Trial of Docetaxel plus Enzalutamide versus Docetaxel as First-line Chemotherapy for Patients with Metastatic Castration-resistant Prostate Cancer: CHEIRON Study

Chicago, IL (UroToday.com) Docetaxel and enzalutamide, along with abiraterone, are FDA approved therapies for the treatment of metastatic castration-resistant prostate cancer (mCRPC). TAX327 was the landmark study which demonstrated that docetaxel could improve overall survival, response to pain, serum PSA, and quality of life over mitoxantrone in patients with mCRPC.1 Since that trial, AFFIRM and PREVAIL demonstrated that enzalutamide could improve overall survival in patients both after and before chemotherapy.2,3 Indeed, both have now demonstrated efficacy in even earlier prostate cancer disease states, including metastatic hormone-naïve prostate cancer.  

However, in the setting of mCRPC, the current standard of care is a choice between enzalutamide, docetaxel and abiraterone - a decision driven by the volume of disease, cost burden, and adverse event profile. Yet, it would seem natural that a combination approach may be more efficacious than monotherapy. Much is unknown about the efficacy of the combination of docetaxel and an androgen-axis targeted therapy. 

In this multi-center, phase II randomized controlled trial (CHEIRON), the authors assess the candidate efficacy of chemo-hormonal combination docetaxel and enzalutamide (D+E) versus docetaxel (D) alone in mCRPC first-line.  

ASCO 2019 CHEIRON study design

As seen above, eligibility criteria included mCRPC diagnosis, ECOG PS ≤ 2, adequate renal, hepatic and hematological functions, and no prior treatment for mCRPC. Patients were randomized to receive either D 75 mg/m2 IV d1 q3w plus prednisone 5 mg PO BID for 8 courses with or without plus E 160 mg PO daily for 24 weeks. Stratification criteria were the presence of pain and visceral metastases. The primary endpoint of the study was the rate of patients without disease progression (according to PCWG2) at 6 months after randomization.  

Between 09/2014 and 10/2017, 246 pts were randomized to either DE (120) or D (126). Full study demographics can be seen below: 

ASCO 2019 CHEIRON baseline pt characteristics

The rate of patients without disease progression at 6 months was significantly higher in DE arm compared to D arm (89.1% vs 72.8%; p = 0.002).  

ASCO 2019 CHEIRON rate of progression
PSA50 (decline in PSA by 50% from baseline) was also higher in the DE arm than the D arm (92.2% vs 70.0%; p < 0.0001). The median progression-free survival with a median follow-up of 25 months was significantly higher in the DE arm than the D arm, 10.1 months vs 9.1 months (p = 0.01) but overall survival was not found to be significantly different, 33.7 months vs 29.6 months. The KM curves are seen below:
ASCO 2019 CHEIRON PFS
ASCO 2019 CHEIRON OS

In terms of adverse event profile, major hematological toxicities consisted of grade 3-4 neutropenia (19 pts DE – 15 pts D); febrile neutropenia was observed in 10 DE pts and in 6 D pts. The full comparison is seen below – clearly favoring docetaxel alone.  
ASCO 2019 grades in pts

This is the first randomized phase II study of docetaxel plus enzalutamide for patients with mCRPC. This trial demonstrates that combining docetaxel and enzalutamide upfront for patients with mCRPC increases median progression-free survival. However, there was no benefit seen for overall survival. Currently, other combinations are being explored with docetaxel, including Pembrolizumab + Docetaxel in Keynote 365. In addition to this combination being studied in the mCRPC space, the combination of the two therapies is currently being studied in the metastatic castration sensitive space with ENZADA.

Presented by: Orazio Caffo, MD, Santa Chiara Hospital, Trento, Italy

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References: 
  1. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine 2004;351:1502-12. 
  2. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 2012;367:1187-97. 
  3. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. The New England Journal of Medicine 2014;371:424-33. 
  4. Burgess EF, Grigg C, Clark PE, Boselli D, Symanowski JT, Raghavan D. A phase II trial of enzalutamide, docetaxel and androgen deprivation therapy (ENZADA) in patients with metastatic castrate-sensitive prostate cancer (mCSPC). American Society of Clinical Oncology; 2018.
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