Mace Rothenberg, MD
Enzalutamide (Xtandi) plus androgen deprivation therapy (ADT) significantly improved radiographic progression-free survival (rPFS) compared with ADT alone, according to topline results of the phase III ARCHES trial (NCT02677896).1
Results of a preliminary safety analysis showed that the safety profile of enzalutamide was consistent with prior studies of the androgen receptor (AR) inhibitor. Full findings of the trial are slated to be presented at an upcoming medical meeting, according to Pfizer and Astellas, the co-developers of enzalutamide.
"While Xtandi is currently approved for both metastatic and nonmetastatic CRPC, there still remains a need for more treatment options for men with metastatic hormone-sensitive prostate cancer," Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development, said in a press release. "With these top-line results, we believe Xtandi has the potential to help men whose disease has progressed outside the prostate gland, but still responds to treatment to lower testosterone."
The international, double-blind, placebo-controlled, phase III trial randomized 1150 patients with metastatic hormone-sensitive prostate cancer to receive enzalutamide at 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone agonist or antagonist, or had a history of bilateral orchiectomy.
To be eligible for enrollment, patients could have low- and high-volume disease, were newly diagnosed with metastatic hormone-sensitive disease, and could have had prior definitive therapy and subsequently developed metastatic disease. Patients also must have had an ECOG performance status of 0 or 1.
ARCHES also included patients who received recent treatment with docetaxel but did not have disease progression. The primary endpoint of the trial was rPFS, defined as the time from randomization to the first objective evidence of radiographic disease progression as assessed by central review, or death, whichever occurs first.
The FDA initially approved enzalutamide in 2012 as a treatment for men with metastatic CRPC following docetaxel. This approval was expanded in 2014 to include treatment with the antiandrogen agent prior to chemotherapy.
In July 2018, the agency approved enzalutamide as a treatment for patients with nonmetastatic CRPC. The decision was based on findings from the phase III PROSPER trial, in which the combination of enzalutamide and ADT reduced the risk of metastases or death by 71% versus ADT alone for patients with nonmetastatic CRPC.2
In the double-blind study, the median metastasis-free survival was 36.6 months with enzalutamide plus ADT versus 14.7 months with ADT alone (HR, 0.29; 95% CI, 0.24-0.35; P
In the metastatic high-risk castration-sensitive prostate cancer setting, abiraterone acetate (Zytiga), a second AR inhibitor, was approved by the FDA in February 2018 in combination with prednisone.
This approval was based on findings from the phase III LATITUDE trial, which showed a 38% reduction in the risk of death with abiraterone acetate/prednisone plus ADT compared with ADT alone.3
Results showed that a median follow-up of 30.4 months, the median overall survival (OS) was not yet reached with abiraterone acetate versus 34.7 months with placebo for patients with high-risk metastatic, castration-sensitive prostate cancer (HR, 0.62; 95% CI, 0.51-0.76; P
In LATITUDE trial, 1199 newly diagnosed patients with high-risk metastatic prostate cancer were randomized to abiraterone acetate, prednisone, and ADT (n = 597) or ADT and placebo (n = 602). Abiraterone acetate was administered at 1000 mg daily, prednisone was given at 5 mg daily, and ADT consisted of a gonadotropin-releasing hormone (GnRH) analog. Patients could not have received prior ADT and had at least 2 of 3 risk factors: Gleason score greater ≥8, measurable visceral metastases, or ≥3 bone lesions.
Results showed that the median rPFS with abiraterone acetate was 33.0 months compared with 14.8 months for ADT alone, representing a 53% reduction in the risk of progression or death (HR, 0.47; 95% CI, 0.39-0.55; P
<.001). The OS rate at 3 years was 66% in the abiraterone acetate group versus 49% with ADT.
- Astellas and Pfizer Announce Positive Top-Line Results from Phase 3 ARCHES Trial of XTANDI® (enzalutamide) in Men with Metastatic Hormone-Sensitive Prostate Cancer. Astellas Pharma Inc. Published December 20, 2018. https://prn.to/2SaGyR5?rel=0" . Accessed December 20, 2018.
- Hussain M, Fizazi K, Saad F, et al. PROSPER: A phase 3, randomized, double-blind, placebo (PBO)-controlled study of enzalutamide (ENZA) in men with nonmetastatic castration-resistant prostate cancer (M0 CRPC). J Clin Oncol. 2018;36 (suppl 6S; abstr 3).
- Fizazi K, Tran N, Fein LE, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352-360.