Three Studies Provide Insights About Combining/Sequencing Abiraterone

Won Kim, MD

Patients with metastatic castration-resistant prostate cancer (mCRPC) who have detectable serum androgen levels despite treatment with ketoconazole experience prostate-specific antigen (PSA) response to subsequent abiraterone acetate, said Won Kim, MD, at the 2014 Genitourinary Cancers Symposium.

Kim’s was one of a number of studies presented during the conference that looked at sequencing or combinations involving abiraterone, including one that considered enzalutamide after abiraterone and another that paired abiraterone with the experimental trebananib.

Abiraterone Active After Ketoconozole

Patients treated with ketoconazole have historically been excluded from phase III clinical trials of abiraterone because these agents have overlapping mechanisms of action—inhibition of CYP17—that have cast doubt on the clinical activity of abiraterone following ketoconazole failure.

“Ketoconazole is less potent and less specific than abiraterone, but it does have overlapping mechanisms of action,” said Kim, a clinical instructor at the University of California, San Francisco. A phase I study of abiraterone in which prior ketoconazole recipients were allowed did show a significant PSA response to abiraterone, leading investigators to examine the utility of abiraterone after ketoconazole in a prospective fashion, Kim said.

An open-label phase II study was conducted in 42 patients with progressive mCRPC who were treated with ketoconazole for at least 28 days prior to enrollment. The median duration of ketoconazole treatment at study entry was 38 weeks. Median PSA level at baseline was 146.2 ng/dL. Ninety percent of patients had bone metastases and 38% had lymph node disease upon entry.

Following 12 weeks of abiraterone treatment at 1000 mg/day, administered with 5 mg of prednisone twice daily, 20 of the 42 patients (48%) had a ≥30% decline in PSA, and 16 patients (38%) had a ≥50% decline in PSA level. In the overall study population, the median time to PSA progression was 16 weeks. The median radiographic progression-free survival (rPFS) was 24 weeks.

“We did an exploratory analysis looking at response according to baseline serum hormone levels, and the most striking finding was that patients who had undetectable levels of DHEA [dehydroepiandrosterone] seemed to respond not so favorably to abiraterone, whereas more than half of the patients who had detectable DHEA levels had a PSA response,” Kim said.

Forty of the patients had DHEA level measured at baseline. Of the nine patients who had a DHEA level below the limit of quantitation on an ultrasensitive assay, only one (11%) had a PSA decline ≥30% at 12 weeks, compared with 17 of 31 (55%) who had DHEA levels above the limit of quantitation.

In addition, a near three-fold increase in rPFS was observed with abiraterone in patients who had detectable versus undetectable DHEA levels (12 weeks vs 31.5 weeks; P = .0009), he said.

Duration of ketoconazole also appeared to affect the response to abiraterone. “The patients who didn’t have a response on abiraterone were on ketoconazole for a long time…whereas patients who experienced a PSA decline on abiraterone were not on ketoconazole for a long time,” he said. “This says that maybe there’s a pharmacokinetic or pharmacodynamic reason why ketoconazole works in some patients and not in others, and maybe that serum androgens can be a marker in patients treated with androgen synthesis inhibitors.” Even at very low testosterone levels, serum androgen levels have been shown to have prognostic value in patients with mCRPC, he said.

After Abiraterone, One-Third of Men with mCRPC Respond to Enzalutamide

A retrospective analysis of 195 patients with mCRPC treated with enzalutamide at seven academic medical centers shows that more than one-third who received prior abiraterone achieved a ≥30% decline in PSA level, reported Heather Cheng, MD.

Of all patients treated with enzalutamide who were evaluable for PSA response (n=183), 42% achieved a ≥30% PSA decline on enzalutamide. Of the 150 patients who received prior abiraterone and were evaluable for PSA response, 39% achieved a ≥30% PSA decline on enzalutamide.

“About 30% of patients who did not respond to abiraterone did respond to enzalutamide, so there are overlapping but also some distinct mechanisms of resistance,” said Cheng, an oncology fellow at the Fred Hutchinson Cancer Research Center, in Seattle, Washington.

“Individual patients may be resistant to both abiraterone and enzalutamide, but not every one,” she said. “Until we understand the molecular signatures, we won’t be able to say, on a patient-by-patient basis, which one should be given first. Hopefully, we’ll get that molecular information, but until then, if you’ve had abiraterone and did not respond, there’s still a possibility you’ll have a good response to enzalutamide.”

Abiraterone + Trebananib Found Safe, Tolerable

Abiraterone used in conjunction with the angiopoietin 1/2 antagonist peptibody trebananib demonstrated a favorable tolerability and acceptable safety profile in nine patients with mCRPC, paving the way for a randomized phase II study of dual targeting of the androgen and angiogenic axis in this population, according to investigators at Walter Reed National Military Medical Center, in Bethesda, Maryland. The National Cancer Institute study is currently accruing chemotherapy-naïve patients to the trial, which will compare outcomes with abiraterone/prednisone plus trebananib versus abiraterone/prednisone alone.

Trebananib is also being explored in the clinic for the treatment of ovarian and other cancers.

References

Kim W, Wilton J, Zhang L, et al. Activity of abiraterone acetate in metastatic patients with castration-resistant prostate cancer previously treated with ketoconazole: A prospective phase II study from the prostate cancer clinical trials consortium. Presented at: the 10^th Annual Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract 53.

Cheng HH, Nadal R, Gulati R, et al. The effect of prior abiraterone use on the activity of enzalutamide in men with mCRPC. Presented at: the 10^th Annual Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract 18.

Ojemuyiwa MA, Karzai FH, Shah AA, et al. A safety study of trebananib (AMG 386) and abiraterone in metastatic castration-resistant prostate cancer. Presented at: the 10^th Annual Genitourinary Cancers Symposium; January 30-February 1, 2014; San Francisco, California. Abstract 218.

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