SAN FRANCISCO ― Statin use may prolong the duration of abiraterone acetate (Zytiga, Janssen Pharmaceuticals, Inc) treatment in men with castration-resistant prostate cancer (CRPC), according to new findings presented here at Genitourinary Cancers Symposium (GUCS) 2016.
In 224 men with CRPC, there was a trend to longer abiraterone duration among statin users: 14.2 vs. 9.2 months (hazard ratio [HR], 0.79; P = .14).
"This was contrary to our initial hypothesis," said lead author Lauren C. Harshman, MD, of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute, in Boston, Massachusetts. She explained that preclinical work had suggested that statins would negatively affect abiraterone because of competition at a cellular level.
The organic anionic transporter SLCO2B1 enables a variety of anticancer compounds and hormones to enter cells, including statins and the adrenal androgen dehydroepiandrosterone sulfate (DHEAS), which is a precursor of more potent androgens, such as dihydroxytestosterone (DHT), she explained to Medscape Medical News. Statins compete with DHEAS for influx through SLCO2B1 and may prolong time to progression of patients receiving androgen deprivation therapy (ADT), but abiraterone, which is an androgen biosynthesis inhibitor, may also undergo SLCO-mediated transport, she pointed out.
The greatest degree of abiraterone inhibition of cell growth occurs in the absence of statin but in the presence of intact SLCO2B1, she said. In the presence of statins, inhibition of cell proliferation by abiraterone is decreased and is concentration dependent.
"But when SLCO2B1 is knocked down, abiraterone's inhibitory effects on cell growth are attenuated," Dr Harshman said.
"So our preclinical work suggested that abiraterone might use SLCO2B1 for transport, and we hypothesized that statins might compete with abiraterone," she added. "But what we found was that the opposite was true."
Trend Toward Treatment Duration
To assess the effect of statins on abiraterone therapy, Dr Harshman and colleagues conducted a retrospective analysis of 224 men treated with abiraterone for CRPC. The patients were drawn from the institution's database.
The majority (96%) of patients had metastatic disease at the time they began treatment with abiraterone; 26% had received prior treatment with docetaxel (multiple brands), and 7% had received prior treatment with enzalutamide (Xtandi, Astellas Pharma, Inc). Almost half of the cohort (41%) also received statins.
Although this was not a randomized trial, the two cohorts were well balanced with respect to baseline clinical and demographic factors, such as Gleason score, local treatment, and site of metastases at the initiation of abiraterone therapy. However, there was a slightly higher incidence of M1 disease in patients who had not received statins (20% vs 11%).
The median duration of abiraterone treatment was 10.7 months (range, <1 - 61 months). At the time of data analysis, 160 (71%) had discontinued treatment.
Median follow-up from starting treatment with abiraterone was 27.8 months.
There was a trend to longer treatment duration in pateints receiving statins, and a similar trend was seen in docetaxel- or enzalutamide-naive patients (HR, 0.75). Prior treatment with docetaxel or enzalutamide use was significantly associated with shorter abiraterone duration.
After the authors adjusted for prior use of docetaxel, enzalutamide, and site of metastases, the relationship between statin use and abiraterone duration remained unchanged (P = .18, HR, 0.81).
Prostate-specific antigen (PSA) levels at the beginning of abiraterone treatment were similar between patients who received statins and those who did not (20.3 ng/dL vs 16.9 ng/dL), and approximately 80% of patients in either cohort experienced a PSA decline (max decline, -80% vs -87%).
Worthy of Review
The mechanism underlying the seemingly positive effect of statins on abiraterone treatment is yet unclear. "It was a positive trend, but not statistically significant, but that is possibly due to the small numbers," said Dr Harshman. "It could also be an additive effect of statins with abiraterone and blocking DHEAS uptake."
Alternatively, statins may inhibit hepatic abiraterone uptake by prolonging drug exposure and increasing effectiveness.
"At any rate, these were intriguing findings, and I think they are worthy of review in a larger dataset, or prospectively," she added. "We are looking at the data in conjunction with another center right now to see if they're consistent, and considering a possible trial."
Approached by Medscape Medical News for an independent comment, Charles Ryan, MD, associate professor of medicine and urology at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, noted that the study showed a trend toward longer duration of activity with abiraterone, although it was not significant.
"More to the point is that androgens enter into cancer cells using a transporter, and the transporter mechanism that abiraterone uses is also blocked by statins," he explained. "Overall, this is a really interesting finding and could be validated with some of the datasets that are out there."
Dr Ryan also pointed out that statins have an effect on survival for men who use them as treatment for cardiovascular disease, and so "we have to look at the relative contribution from that. The provocative thing is that they are well tolerated and widely used, and this is a reasonable biological hypothesis as to why this can work."
Dr Harshman serves in a consulting or advisory role with Dendreon, Medviation/Astellas, Pfizer, Bristol-Myers Squibb, NCCN, PlatformQ Health, and Genentech and has received research funding from Medivation/Astellas and Bayer. Several coauthors also have relationships with industry, as noted in the abstract.
Genitourinary Cancers Symposium (GUCS) 2016: Abstract 196. Presented January 7, 2016.
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Cite this: Statins Boost Abiraterone Activity in Prostate Cancer - Medscape - Jan 12, 2016.