DHEA levels may predict response to advanced PCa agent

September 29, 2014

Results of a phase II study from the Prostate Cancer Clinical Trials Consortium show that abiraterone acetate (ZYTIGA) has modest clinical activity in men with progressive metastatic castrate-resistant prostate cancer previously treated with ketoconazole.

San Francisco-Results of a phase II study from the Prostate Cancer Clinical Trials Consortium show that abiraterone acetate (ZYTIGA) has modest clinical activity in men with progressive metastatic castrate-resistant prostate cancer (mCRPC) previously treated with ketoconazole.

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Perhaps more noteworthy, however, was the finding from an exploratory analysis indicating that men were unlikely to benefit from abiraterone if their plasma dihydroepiandrosterone (DHEA) level at treatment initiation measured by liquid chromatography/mass spectrometry (LC/MS) was below the assay’s limit of quantitation, reported first author Won Kim, MD, at the American Society of Clinical Oncology annual meeting in Chicago.

 

Next: "The study shows that there are men who benefit from abiraterone despite prior CYP17 inhibition."

 

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“Abiraterone and ketoconazole may have overlapping mechanisms of resistance, but this has never previously been evaluated in a prospective clinical trial. The study shows that there are men who benefit from abiraterone despite prior CYP17 inhibition. Currently, however, that finding has limited clinical relevance since, at least in the United States, very few men with mCRPC will be started on ketoconazole,” explained Dr. Kim, assistant clinical professor of medicine, division of hematology/oncology at the University of California, San Francisco.

“The finding associating baseline DHEA with response to abiraterone is of greater interest and merits further investigation, both to determine the role of DHEA and other circulating androgens as a potential biomarker and for understanding mechanisms of abiraterone action and resistance.”

The phase II study enrolled 42 men who were chemotherapy-naïve and had received ketoconazole for a minimum of 28 days. Other eligibility criteria required they have a testosterone level <50 ng/mL, normal baseline organ function, and a normal cortisol response to ACTH stimulation testing.

Men were treated with abiraterone, 1,000 mg daily, and prednisone, 5 mg twice daily until radiographic progression, which was defined as death, disease progression by RECIST or PCWG-2 criteria, or unequivocal clinical progression.

Baseline characteristics showed the men had used ketoconazole for a median of 43 weeks and had a median PSA of 48.5 ng/dL. Except for two men who stopped ketoconazole for Grade 3/4 toxicities, all others discontinued it because of prostate cancer progression.

Of 39 evaluable patients, 20 (51%) achieved the primary outcome endpoint of a ≥30% decline in PSA at 12 weeks, while 16 (41%) achieved a ≥50% decline at 12 weeks. Overall, radiographic progression-free survival (rPFS) for the group was 35.9 weeks. Median duration of ketoconazole treatment was significantly shorter among men who achieved the primary endpoint compared to those who did not (20 vs. 72 weeks, respectively).

Abiraterone acetate was well tolerated, and its safety profile was similar to that seen in men without prior ketoconazole treatment.

Higher DHEA levels linked to better outcomes

Data from the LC/MS analysis showed baseline circulating DHEA levels were above the assay’s limit of quantitation (LOQ) in 29 men and below the LOQ in eight men. Comparisons of outcomes between those two subgroups showed statistically significant differences that favored men with detectable DHEA for having a higher primary endpoint response rate (59% vs. 11%), longer median time to PSA progression (16 vs. 6 weeks), and longer rPFS (36.0 vs. 13.7 weeks).

One of Dr. Kim’s co-authors has an employment or leadership position with and owns stock in Johnson & Johnson, and another of his co-authors has received honoraria from Janssen Biotech.UT 

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