Abiraterone acetate in combination with low-dose prednisone (5 mg) significantly lowered PSA levels with a consistent toxicity profile in men with high-risk nonmetastatic castration-resistant prostate cancer.
E. David Crawford, MD
Abiraterone acetate (Zytiga) in combination with low-dose prednisone (5 mg) significantly lowered PSA levels with a consistent toxicity profile in men with high-risk nonmetastatic (M0) castration-resistant prostate cancer (CRPC), according to findings from the IMAAGEN study at the 2015 AUA Annual Meeting.1
Findings were reported from 122 evaluable men enrolled in the phase II study between May 2011 to July 2013 at 38 sites in the United States. By the end of six 28-day cycles of treatment, 87% (106/122) of patients showed a PSA reduction of ≥50% and 60% (73/122) achieved a ≥90% PSA reduction. The PSA progression-free rates at 12, 18, and 24 months were estimated at 82.4%, 73.5%, and 62.8%, respectively.
“There have been a number of important presentations that have come from this innovative trial,” study coauthor E. David Crawford, MD, professor of surgery, urology, radiation oncology, University of Colorado, Denver, said in an interview withTargeted Oncology. “This phase II clinical trial was aimed at evaluating treatment with abiraterone acetate and low-dose prednisone5 mg, not the 10 mg [dose] used in the other abiraterone trials—on patients with nonmetastatic CRPC.”
Abiraterone plus 10-mg prednisone is FDA-approved as a treatment for men with metastatic CRPC. In March 2015, the FDA updated the label for abiraterone to include data from the final analysis of the phase III COU-AA-302 study, which detailed a significant prolongation in overall survival with the drug compared with placebo. The FDA initially approved abiraterone in combination with 10-mg prednisone in 2011.
The phase II IMAAGEN included 131 men who were at high risk of developing metastasis. Patients were required to have PSA levels ≥10 ng/mL or a PSA doubling time of ≤10 months at screening. The median age was 72 years (48-90), and the median baseline PSA was 11.9 ng/mL (1.3-167.8 ng/mL). Data cutoff for the analysis was December 31, 2013.
The primary endpoint of the study was PSA response rate at 6 months, and main secondary endpoints were: change in testosterone levels, time to PSA progression, time to radiographic disease progression, and safety. PSA assessment and imaging scans were conducted every 3 months.
“Patients with non-metastatic CRPC frequently progress to metastatic CRPC. The patients in this study had clinical features placing them at higher risk of developing metastatic disease. We sought to understand the impact of treatment with abiraterone acetate plus prednisone (5 mg once daily) on PSA response, which is one factor to consider when evaluating disease progression,” lead investigator Charles Ryan, MD, professor of Clinical Medicine, Urology at the University of California, San Francisco, said when results from the study were initially presented at the 2014 ASCO Annual Meeting.
Radiographic progression-free survival rates at 12, 18, and 24 months were 89%, 87%, and 87%, respectively. Mean testosterone levels were reduced by approximately 96% after 3 and 6 cycles of treatment.
Twenty-three patients (17.6%) experienced PSA progression. At the time of data cut off, median time to PSA progression was not estimable.
The drug was fairly well tolerated, according the Crawford. “What was important about the safety profile using 1000 mg [abiraterone] with 5 mg of prednisone was that it was similar to what had been reported with 1000 mg [abiraterone] and 10 mg of prednisone,” Crawford said.
Adverse events (AEs) occurred in 92.4% of patients (43.6% had a grade 3 or higher AE), and 29.0% of patients experienced a serious AE (27.5% grade 3 or higher). 10.7% of patients discontinued treatment as a result of AEs. Four patients had AEs resulting in death; these AEs included coronary artery disease, myocardial infarction, acute respiratory failure, and pneumonia.
"The main reason the prednisone is given is to help minimize the hypokaylemia that can be caused by the suppression of the steroid hormone pathway, and you end up with excess production of aldosterone," Leonard G. Gomella, professor and chairman of the Department of Urology at the Sidney Kimmel Cancer Center, Thomas Jefferson University, said in an interview withTargeted Oncology. "By giving a very low dose of prednisone, what you really do is you keep the aldosterone level from rising and hopefully limit the side effect of hypokaylemia."An award-winning poster also presented at the AUA Annual Meeting detailed a high rate of unsuspected asymptomatic metastatic disease, which was found during screening for the IMAAGEN trial.2During screening, patients who met entry criteria based on laboratory results underwent imaging to screen for local disease progression or metastatic disease. The study authors used this information to identify patients at high risk for progression from non-metastatic to metastatic disease.
Out of the 298 patients who were screened, 167 (56%) patients had screen failure, and 77 patients had metastatic disease. “Of the men who were screened for this study, nearly 40% of them had metastatic disease. These were men who we thought were thought good candidates for this study and who we [initially] thought did not have metastatic disease,” Crawford said.
The study authors concluded, “These findings suggest the need to prospectively define risk factors for development of metastatic disease in CRPC to assure timely identification, especially in light of new treatment options.”Janssen, the manufacturer of abiraterone, has focused their attention on developing the novel antiandrogen ARN-509 as a potential treatment for CRPC, including nonmetastatic disease. In a cohort of 51 patients with M0 CRPC, ARN-509 demonstrated PSA responses at 12, 24, and 36 weeks of 91%, 87%, and 48%, respectively, according to data presented at the AUA meeting.3The most common all-grade AEs, most of which were grade 1/2, were fatigue (57%), diarrhea (41%), nausea (29%), dysgeusia (20%), arthralgia (18%), and weight decreased (16%).
The phase III SPARTAN trial is examining ARN-509 in comparison with placebo as a treatment for men with M0 CRPC. The study plans to enroll 1200 participants (NCT01946204). The primary endpoint of the investigation is metastasis-free survival, with secondary outcome measures focused on overall and progression-free survival.