More men with castration-resistant prostate cancer saw their prostate cancer antigen (PSA) levels — a marker of the disease — decline when they took Xtandi (enzalutamide) after Zytiga (abiraterone acetate) than did those who took the medications the other way around, according to results from a Phase 2 clinical trial.
In the randomized, crossover trial (NCT02125357), researchers in Canada sought to determine whether there was an optimal sequence for taking these two inhibitors of androgen signaling, which, despite their wide use, hadn’t been directly compared against each other in a clinical trial.
The trial showed that when deciding first- and second-line treatment for men with advanced prostate cancers, Zytiga should be offered first, and patients should switch to Xtandi after showing signs of progression on their initial therapy.
Findings were published in the study, “Optimal sequencing of enzalutamide and abiraterone acetate plus prednisone in metastatic castration-resistant prostate cancer: a multicentre, randomised, open-label, phase 2, crossover trial,” in The Lancet Oncology.
Metastatic castration-resistant prostate cancer (mCRPC) is cancer that has spread to distant sites and progresses despite the successful suppression of cancer-stimulating male hormones (androgens) such as testosterone.
Men with mCRPC are offered second-line hormone therapies, including Zytiga (marketed by Janssen Biotech) and Xtandi (marketed by Astellas Pharma) that directly target the androgen pathway. The two medicines work against mCRPC in similar ways, and either can be used as a first-line treatment.
The availability of two equally effective therapies gives patients the option to switch if they fail to respond to one or the other medicine. However, it was uncertain whether patients treated with Xtandi as a second-line therapy to Zytiga experience more benefits than those treated with Zytiga as a second-line therapy to Xtandi.
To determine this, the Phase 2 trial enrolled 202 adults who had never received either Zytiga or Xtandi. Of these, 101 were given a daily dose of 1,000 mg of Zytiga, along with two daily 5 mg doses of prednisone (an add-on steroid for prostate cancer treatment).
When a patient showed a rise in PSA levels or other clinical signs of disease progression, he was switched to 160 mg of Xtandi per day. The remaining 101 patients were given the opposite sequence of treatments.
PSA levels were tested every four weeks, and computerized tomography (CT) scans of the chest, abdomen, and bones were conducted once every 12 weeks.
The primary goal of determining which therapy provided more benefits as a second-line treatment was measured using the proportion of patients who attained a PSA response (a 30% or more reduction in PSA levels) and the time to PSA progression on second-line therapy.
At the time of the analysis, 73 patients on first-line Zytiga had switched to Xtandi, and 75 patients initially on Xtandi were receiving Zytiga.
There was no difference between the two medicines when used as first-line therapy, as the time to first PSA progression was similar in both groups.
However, patients on second-line Xtandi lived significantly longer without a rise in PSA levels (median of 19.3 months) than those on second-line Zytiga (15.2 months).
PSA responses were also better when Xtandi was used second — 36%, compared with 4%.
Overall survival was not statistically significant among the two groups, with patients on second-line Xtandi living a median of 28.8 months, compared with 24.7 months for those on second-line Zytiga.
Adverse events were consistent with the known safety profile of each medicine. High blood pressure and fatigue were the most common serious side effects, seen with both first and second-line treatment, and were similar for Zytiga and Xtandi.
“[Xtandi] showed activity as a second-line novel androgen receptor pathway inhibitor, whereas [Zytiga] did not, leading to a longer time to second PSA progression for the sequence of abiraterone followed by enzalutamide than with the opposite treatment sequence,” the researchers said.
“Our data suggest that using a sequencing strategy of [Zytiga] followed by [Xtandi] provides the greatest clinical benefit,” they said.