Safety Data Confirmed in Abiraterone, Low-Dose Prednisone Combo Trial

Charles J. Ryan, MD

Men with nonmetastatic castration-resistant prostate cancer (nmCRPC) demonstrated a median time to prostate-specific antigen (PSA) progression of 28.7 months and a median time to radiographic progression of 41.4 months, according to updated safety and efficacy data involving abiraterone acetate (Zytiga) and low-dose prednisone.

The primary endpoint of the study, a 50% reduction in PSA levels, was achieved by 87% (n = 131) of patients with nmCRPC, with 60% of patients achieving a ≤90% reduction in PSA levels at the time of data cutoff, according to a poster presented during the 2016 ASCO Annual Meeting.¹

The findings were nearly identical to those reported in a poster presented in 2014, with the exception of serious adverse events.²The current poster recorded a high rate of serious AEs, which was not reported in 2014.

“There are two important points about this research: first, it’s safe to give abiraterone acetate with a reduced dose of 5 mg of prednisone, and second, we did not reach the median time to metastasis,” said lead author Charles J. Ryan, MD, professor of Clinical Medicine and Urology and Program Leader, Genitourinary Medical Oncology, at the UCSF Helen Diller Family Comprehensive Cancer Center.

Abiraterone acetate is standard of care for metastatic disease. “Most nonmetastatic patients ultimately progress, and there is no approved therapy for this population,” said Ryan.

In the current phase II, single-arm study, 131 patients received 1000 milligrams of abiraterone acetate with prednisone daily for 28 days. Individuals were excluded if they were using anti-androgen therapy at the time, if they had previously used CYP17 inhibitors, or aminoglutethimide (NCT01314118).

The study consisted of a screening phase (up to 4 weeks), a core study treatment phase (comprised of 6 28-day cycles), a pre-metastatic disease follow-up phase, and an optional post-metastatic disease follow-up phase.

Men who have not had radiographic confirmed disease progression after the core study treatment phase will continue the study treatment in the pre-metastatic disease follow-up phase. Once disease progression is confirmed, patients will have an option to continue the study treatment and are able to receive subsequent anticancer therapy as clinically needed in the post metastatic disease follow-up phase. The study will end when all participated subjects have disease progression.

The median subject age was 72 years old. Twenty subjects discontinued treatment prior to the seventh cycle. The median time of exposure to the drug was 22.1 months, and estimated median follow-up was 40 months.

Among those patients who completed 6 cycles of treatment, 33 discontinued for reasons other than progression or death, including 3 due to adverse events, 10 due to physician decision, and 3 due to protocol violations, according to the poster. Seventeen patients withdrew consent.

In addition to its primary endpoint (PSA reduction), secondary endpoints included time to PSA progression, time to radiographic progressive disease, and safety. Fifty-six patients (42.7%) showed evidence of PSA progression.

However, there were not enough events to determine the median time to radiographic progression, the researchers noted. “Fewer than half of the patients developed metastases, even after this long follow-up,” explained Ryan.

When researchers considered a sensitivity analysis that included 15 additional unconfirmed progressions that led to initiation of new therapy, they determined that 23.7% of patients showed radiographic evidence of progression, and calculated that the median time to progression was 41.4 months.

Safety was also a secondary endpoint. “There was some concern that the long-term dose of prednisone could have toxicity, such as potential weight gain, cataracts, skin fragility, and edema,” Ryan said. The researchers concluded that the safety profile of the combination is consistent with the safety profile from previously reported studies of abiraterone acetate in combination with either 5 or 10 mg prednisone.

Adverse events (AEs) were reported in 96.2% of patients, which was grade 3 or higher in 61.1%. AEs resulted in study termination in 15.3% of patients, including 7 deaths (5.3% of the study population), from causes such as acute respiratory failure, sepsis, pneumonia, coronary artery disease, myocardial infarction, and congestive heart failure, according to the researchers. Of the original cohort of 131 subjects, 33.6% (44 patients) remained on study treatment at the time of the study cut-off.

Ryan C, Crawford E, Shore N, et al. IMAAGEN trial safety and efficacy update: Effect of abiraterone acetate and low-dose prednisone on prostate-specific antigen and radiographic disease progression in patients with nonmetastatic castration-resistant prostate cancer.J Clin Oncol.34, 2016 (suppl; abstr 5061).

Ryan C, Crawford E, Shore N, et al. Effect of abiraterone acetate and low-dose prednisone on PSA in patients with nonmetastatic castration-resistant prostate cancer: The results from IMAAGEN core study.J Clin Oncol.32:5s, 2014 (suppl; abstr 5086).