Drug Interactions and Dosing Issues Complicate Newly Approved mCRPC Therapies

Robert Dreicer, MD

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 inClinical Pharmacokinetics,¹serves 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 paper 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 withTargeted Oncology. “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 mCRPC.

“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 effect 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 done 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 clinicaltrials.gov.

Other commonly-used drugs which may have interactions with abiraterone acetate and enzalutamide include the commonly prescribed cholesterol agent gemfibrocil, 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%.²Therefore, 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 post-marketing safety trial to assess the risk.

“Enzalutamide crosses the brain-blood barrier and competes with chloride channels in GABA receptors. Seizure activity was seen in the AFFIRM trial in 0.9% of patients on enzalutamide and 0.1% of patients, 1 to be exact, in the PREVAIL trial. However, the neurocognitive dysfunction from enzalutamide is far more important than seizure activity (just by incidence),” explained Garcia in an email interview.

Dosing According to Bioavailability Factors

Not only are drug interactions a potential issue for abiraterone acetate and enzalutamide, but research shows that several factors beyond co-administration may affect the drugs’ activity, opening up the possibility for a wide variety of dosing strategies that have not yet been sufficiently researched, according to the review.

Due to a wide variation in the bioavailability of abiraterone, “hypothetically, a subgroup of patients will be undertreated at the normal dose of 1000 mg once daily,” researchers noted.³

On the other hand, according to several studies cited by the article, the bioavailability of the drug was between 2 and 17 times greater in patients who took the drug after a meal, compared with those who took the drug without food, although regulators recommend that abiraterone acetate be taken in fasting conditions. These findings merit further research, according to the article.

Yet again, the authors noted that oncologists have sometimes used a drastically reduced dose of abiraterone in patients with severe hepatic impairment. In one such study, patients with severe liver impairment received a greatly reduced dose (125 mg) compared with the healthy volunteers (2000 mg), the article noted. Other research showed that the half-life of the drug only increased by a little over three hours, even in patients with severe renal impairment.

Notwithstanding the dosing and drug interaction issues, these two agents have provided a much-needed line of treatment options for patients with advanced disease. Yet neither drug is a cure.

“These drugs are pretty amazing; they’ve really revolutionized the way we treat prostate cancer,” said David Jarrard, MD, professor of urology at the University of Wisconsin Carbone Cancer Center. “Both are well-described and have been studied in tens of thousands of patients. The interactions can be managed just by keeping an eye on the patient’s liver function tests to make sure patients don’t get in trouble.”

Neither age, testosterone levels, nor BMI have been shown to affect abiraterone exposure, and the drug appears to have the same pharmacokinetics in Asians as in Caucasians.

But research is lacking for other biomarkers, the article said, noting that “[n]o formal studies have been conducted to assess the influence of age, weight, height, or genetic polymorphisms on drug exposure and treatment response.”

“The biggest questions right now are, ‘What is the appropriate sequence and what is the right phenotype?’” explained Garcia.

For example, in a 2014 study of 62 men with prostate cancer patients, researchers showed that a mutation in the androgen-receptor isoform encoded by splice variant seven, which lacks the ligand-binding domain that enzalutamide and abiraterone target, plays an important role in the effect of both drugs.⁴

“They proved that if patients have that variant, the likelihood of benefit from either drug is close to zero,” noted Garcia.

“Both drugs are in a myriad of clinical trials, particularly in combination with other novel agents such as sipuleucel, radium 223, and likely upcoming studies with PARP inhibitors,” added Dreicer.

References:

1. Benoist G, Hendriks R, Mulders P, et al. Pharmacokinetic Aspects of the Two Novel Oral Drugs Used for Metastatic Castration-Resistant Prostate Cancer: Abiraterone Acetate and Enzalutamide. [Published online April 22, 2016.]Clin Pharmacokinet.doi:10.1007/s40262-016-0403-6.
2. Gibbons JA, de Vries M, Krauwinkel W, et al. Pharmacokinetic drug interaction studies with enzalutamide.Clin Pharmacokinet.2015;54(10):1057-1069.
3. European Medicines Agency. European Public Assessment Report (EPAR): Zytiga (abiraterone acetate). London: European Medicines Agency; 2016.
4. Antonarakis ES, Lu C, Wang H, et al. AR-V7 and Resistance to Enzalutamide and Abiraterone in Prostate Cancer.N Engl J Med.2014;371(11):1028-1038.