Some men with advanced prostate cancer have been given the antifungal treatment Ketoconazole (Keto) as a second line hormone treatment. Like Keto, this newer hormone treatment that is now available, Abiraterone acetate (AA) (Zytiga) works by inhibiting CYP17, the rate-limiting enzyme in androgen biosynthesis.
The question being asked, if Keto has failed ,given its similar mode of action, can Zytiga still be an active agent? In the clinical trials for Zytiga men with prior keto treatment were excluded, so the utility of Zytiga after Keto is not well understood.
In a prospective study the researchers evaluated the efficacy of Zytiga in men who had received prior Keto. The trial consisted of men with progressive castration-resistant prostate cancer (mCRPC) who had prior Keto therapy for 28 days or more and who were treated with Zytiga at 1,000 mg and prednisone 5 mg daily.
Serum androgen levels, including dehydroepiandrosterone (DHEA), were measured at baseline and during treatment for exploratory analyses. Radiographic progression-free survival (rPFS) was defined as freedom from: death, radiographic progression, or unequivocal clinical progression.
The trial enrolled forty two men. Median age was 71. Median prostate-specific antigen (PSA) was 47.5ng/dL. Median duration of prior keto was 38 weeks (range 5 to 207).
Treatment with Zytiga resulted in:
1- A 30% or greater decline in PSA at 12 weeks in 20 men (48%, 95% CI, 32-63%).
2- A 50% or greater decline in PSA at 12 weeks in 16 men (38%, 95% CI 24-54%).
3- Median time to PSA progression (TTPP) was 16 weeks (range 4 to 64).
4- Median rPFS was 24 weeks (range 1 to 88).
5- Baseline serum DHEA levels were measured in 40 men. Nine men had DHEA less than the limit of quantitation (LOQ, 0.250ng/mL), and 31 men had DHEA greater than or equal to LOQ.
6- One man with DHEA less than LOQ had PSA decline 30% or more at 12 weeks, compared to 17 men (17 out of 31, 55%, 95% CI 36-72%) with DHEA greater than or equal to LOQ (p=0.028).
7- Median time to pain progression (TTPP) was 8 weeks (range 4 to 32) for men with DHEA less than LOQ, compared to 18 weeks (range 4 to 64) for men with DHEA greater than or equal to LOQ (p=0.012).
8- Median rPFS was 12 weeks (range 4 to 24) for men with DHEA less than LOQ, compared to 36 weeks (range 1 to 88) for men with DHEA greater than or equal to LOQ (p = 0.0006).
9- Six men remain on Zytiga.
The study found that a significant proportion of the men with prior Keto exposure demonstrate a clinical response to Zytiga. So, if you have had Keto in your treatment protocol you should still try Zytiga as a treatment.
Clinical trial information: NCT01199146.
2014 Genitourinary Cancers Symposium
Abstract No: 53
Citation: J Clin Oncol 32, 2014 (suppl 4; abstr 53)
Author(s): Won Kim, John Wilton, Li Zhang, Amy M. Lin, Lawrence Fong, Terence W. Friedlander, Andrew Caleb Hsieh, Rahul Raj Aggarwal, Tammy J. Rodvelt, Allison Morse, Jeffrey Bozeman, Vivian K. Weinberg, Arturo Molina, James Mohler, Gerald J. Fetterly, Russell Zelig Szmulewitz, Eric Jay Small, Charles J. Ryan; University of California, San Francisco, San Francisco, CA; Roswell Park Cancer Institute, Buffalo, NY; The University of Chicago Medical Center, Chicago, IL; Janssen Research & Development, LLC, Menlo Park, CA; The University of Chicago, Chicago, IL
Joel T Nowak, M.A., M.S.W.