Robert Dreicer, MD
Approximately four years after the FDA approval of two powerful new oral androgen-targeting agents for metastatic castration-resistant prostate cancer (mCRPC), an analysis raised issues complicating treatment with the two drugs, as well as what oncologists don’t yet know.
The paper, published in Clinical Pharmacokinetics
serves to heighten clinical awareness of the potential for both under-treatment and over-treatment with abiraterone acetate, as well as potential drug-drug interactions with both abiraterone acetate and enzalutamide.
The study also takes a position on a discrepancy between the labeling approvals by the FDA and EMA. While regulatory agencies of both regions suggest that clinicians should avoid using enzalutamide along with strong CYP3A inducers such as oxycodone or methodone, the FDA suggests that an elevated dose of the cancer drug may be feasible when such co-administration cannot be avoided. In the article, the authors hypothetically adopt the FDA’s position.
Common Drug-Drug Interactions May Be Manageable
“Prostate cancer patients tend to be in their sixth, seventh, and eighth decades of life, so some of them are on many medications,” said Robert Dreicer, MD, professor of medicine and urology at the University of Virginia, who commented on the paper in an interview with Urologists in Cancer Care. “But I don’t look at this as a deal breaker. Most of the time the interactions can be managed without having to stop the other drugs.”
Abiraterone acetate and enzalutamide are thought to work by blocking secondary processes for prostate cancer growth. The primary treatment for patients with prostate cancer is to block the production of testosterone (the hormone that initially drives the tumor), but all patients will ultimately develop resistance. “As to how cancer cells become resistant to the lack of testosterone, there are many hypotheses,” said Jorge Garcia, MD, department of Hematology and Oncology, Cleveland Clinic.
“The first source of growth for the tumor is the androgen receptor, an antenna activated by the male hormone testosterone, but in the absence of that hormone, how can you still have growth through that antenna? Another pathway is the adrenal gland, which produces early androgens that can mimic testosterone and therefore activate the receptor,” explained Garcia, who is the principal investigator in an ongoing clinical trial of enzalutamide following radical prostatectomy (NCT01927627).
While oncologists have used androgen-targeting agents before, the two newer agents are more powerful, and unlike the previous intravenous drugs, are available in oral form. However, both drugs affect the CYP system of enzymes, and are metabolized in the liver.
“Many drugs do that, so if the drugs are competing for the same breakdown pathway, the drug may be metabolized more slowly,” explained Dreicer.
In conducting their review of available literature, researchers Benoist et al conducted a search of the PubMed and EMBASE databases for full-text articles in English describing studies conducted in humans, and published no later than February 22, 2016, for a total of 22 papers. Benoist and colleagues also included registration data from the regulatory agencies and data from the website Clinicaltrials.gov.
Other commonly used drugs which may have interactions with abiraterone acetate and enzalutamide include the commonly prescribed cholesterol agent gemfibrozil, rifampicin (prescribed for tuberculosis), the cough suppressant dextromethorphan, the diabetes drug pioglitazone, and, potentially, acid-reducing agents for GERD.
According to a drug interaction study carried out by Gibbons and colleagues, gemfibrozil, a CYP2C8 inhibitor, increased the exposure of enzalutamide 2.2-fold. Itraconazole increased the exposure 1.3-fold, and rifampicin decreased the exposure by 66%.2
Therefore, the dosage of enzalutamide should be reduced to 80 mg per day when used in combination with CYP2C8-inhibiting drugs, according to the reviewers.
While an older prostate cancer drug, ketoconazole, also has an inhibitory effect on abiraterone acetate, it is not commonly used in patients on the newer agent, so the effect is clinically irrelevant, the paper said.
Additionally, not only should care be taken when co-administering enzalutamide with anti-seizure medication, but enzalutamide has also been associated with seizures even in patients without a known seizure disorder, Gibbons et al wrote in the article. The authors noted that regulators had requested a postmarketing safety trial to assess the risk.