Eleni Efstathiou, MD, PhD
Co-targeting metastatic castrate resistant prostate cancer (mCRPC) with the combination of enzalutamide plus abiraterone acetate may circumvent the compensatory mechanisms observed with either agent alone and lead to more profound suppression of androgen signaling, according to findings of a new study presented at the 2013 European Cancer Congress.
“We are now moving to the concept that CRPC is largely driven by androgen signaling that is amplified as a result of therapy,” Eleni Efstathiou, MD, PhD, associate professor of Genitourinary Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston, told delegates. In several studies, Efstathiou and colleagues first demonstrated that treatment with abiraterone acetate, an androgen biosynthesis inhibitor, reduced testosterone levels in the blood and bone marrow to undetectable levels.
“Soon after initiation of treatment, however, we observed a compensatory feedback mechanism leading to an increase in androgen receptor copy numbers as a result of testosterone depletion,” she said. Similarly, following inhibition of nuclear androgen receptor (AR) localization with enzalutamide (an AR inhibitor), they observed an induction of testosterone both in the blood and bone marrow—“suggesting that there is a feedback mechanism leading to an increase in testosterone,” she added.
They thus tested the hypothesis that a “two-component” approach may be able to cancel out the compensatory response of mCRPC to either drug alone.
A total of 57 evaluable patients with mCRPC with metastases to the bone have been enrolled in the study to date. Patients received 160 mg of once-daily enzalutamide, plus abiraterone acetate (1 g/day), plus prednisone, 5 mg, twice daily. Patients were monitored every 4 weeks for blood and ECG irregularities, while immunohistochemistry was used to assess the effect of the combination strategy on the tumor microenvironment. PSA levels were primarily used to assess disease progression. More than 70% of the group had a Gleason score of ≥8 on enrollment, and 41% had ≥20 bone lesions. The median baseline PSA concentration was 23.3 ng/mL, (range, 1-606.3 ng/mL).
“No new safety concerns have arisen,” Efstathiou said. Two patients discontinued treatment due to adverse events, but no grade 4 or 5 toxicities have been observed thus far—a sign that the combination approach is reasonably well tolerated, she added.
In 49 patients evaluable for disease impact, investigators also noted significant declines in PSA levels. At a median of 5.5 months of treatment exposure, approximately 45% of the 49 evaluable patients had a 90% or greater decline in PSA from baseline. Three-quarters of the group achieved a 50% or greater decline in PSA values from baseline while approximately 84% achieved a 30% or greater decline from baseline PSA values.
“These findings confirm the hypothesis that co-targeting mCRPC with enzalutamide and abiraterone acetate avoids the adaptive response observed with either agent alone and suggest that the combination may have a more profound response rate than either agent alone and that it is well tolerated,” the researchers concluded. Discussant Gerhardt Attard, MD, PhD, Cancer Research UK Clinical Scientist, Royal Marsden NHS Foundation Trust, UK, agreed with MD Anderson investigators that their study confirms the tolerability of the combination.
Nevertheless, he cautioned that comparable declines in PSA in comparable proportions of patients have been reported by other investigators following treatment with either drug alone.
“This is only a single-arm study of 2 highly active drugs, and this really limits any conclusion on the increased activity of the 2 drugs given together,” he said.
A more definitive answer is expected from the ALLIANCE study in men with mCRPC who have not yet received docetaxel. Men will receive either enzalutamide or enzalutamide plus abiraterone acetate. The study is ongoing and the primary endpoint will be overall survival.
Efstathiou E, Titus M, Wen AS, et al. The effects of enzalutamide (ENZA) in combination with abiraterone acetate (AA) in patients with bone metastatic castration resistant prostate cancer (mCRPC). Presented at: European Cancer Congress 2013; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 2854.
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