Deliver Androgen Blockade at Prostate Cancer Cells to Achieve Castrate Levels

Adam S. Kibel, MD

Hormone therapies for prostate cancer aimed at reducing serum androgens are trained on the wrong target: the testes and the adrenal glands. Rather, they should attack the prostate cancer cells themselves, said Adam Kibel, MD, at the 2015 LUGPA Annual Meeting.

“We are very good at driving serum testosterone down to nothing, but it hasn't translated to an improvement in overall survival,” said Kibel, who is chief of Urology in the division of urologic surgery at Brigham and Women's Hospital.

“We have thought that if we kill enough cells, the few that are left will die as well, and maybe that's true, but not by attacking at the level of the blood. Prostate cancer cells make their own androgens, and that's where we need to achieve castrate levels.”

He cited a 2008 study showing that metastatic tissues after chemical or surgical castration had up to four times the amount of testosterone as normal cells.

“We should be doing this, because we understand the disease, we see these patients, and we're not just surgeons,” Kibel said. “We were giving them medications to control their BPH before we diagnosed them with cancer.”

Kibel described in detail the use of two specific agents: the steroidal antiandrogen abiraterone acetate (Zytiga), and the nonsteroidal antiandrogen enzalutamide (Xtandi).

Cancer cells can elude many androgen deprivation strategies in several ways: by making their own testosterone; by increasing their numbers of androgen receptors to take advantage of the few androgens still available at castrate levels; and by mutating to take advantage of other types of steroids. “The cancer cell figures out how to beat a drug, and regrows, and the next thing we know we're fighting more aggressive cells,” Kibel said.

Abiraterone works by blocking testosterone production within the cell, and was approved by the FDA in an expedited review in 2011 because when taken with prednisone it improved overall survival rates compared with prednisone alone. The trial was stopped early because the improvement was so significant. Patients on the combination regimen survived progression-free for 16.5 months compared with only 8.3 months for those on prednisone alone, and the latter group survived an average of 27.2 months in all. The study was stopped before obtaining an average survival rate on the group receiving abiraterone.

In two separate trials, the drug showed good results both with patients who had previously received chemotherapy with docetaxel and those who had not.

The “nuts and bolts” of administering abiraterone include:

· Take on an empty stomach: no food for 2 hours before or 1 hour after

· Swallow the (very large) tablets whole

· Monitor patients for hypertension, hypokalemia, liver toxicity, and fluid retention.

Liver function tests should be done every 2 weeks for the first 3 months, and monthly thereafter. If the tests show toxicity, the manufacturer recommends stopping the drug and then starting again at a lower dose, but Kibel advised attendees to consider bringing in a medical oncologist instead. He also recommended having a specific person in the practice responsible for prescribing and monitoring these drugs, if the practice doesn't already have an oncologist.

Abiraterone can have significant interactions with several drugs, including phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, and phenobarbital. Kibel noted that abiraterone can increase the level of some drugs, including the common cough suppressant dextromethorphan.

Enzalutamide works by blocking androgen receptors, and blocks them almost as well as dihydrotestosterone itself, Kibel said. It inhibits the binding of androgens to the receptors, as well as nuclear translocation of androgen receptors to the cell nucleus and association of the androgen receptors with DNA. A trial of enzalutamide versus placebo in patients who had previously had chemotherapy with docetaxel showed a median survival rate of about 5 extra months. A similar trial is in progress for patients who have not had chemotherapy.

Enzalutamide may be taken on either an empty or a full stomach, but must also be swallowed whole. Blood pressure and CBC should be monitored, and patients should be told to contact their physician if they experience seizure, headache, lethargy, confusion, or blindness—all symptoms of a rare side effect called Posterior Reversible Encephalopathy Syndrome. "I've never seen this side effect, but it looks like it progresses really fast," Kibel said. Fatigue, the most common side effect noted in the trial, is also likely to show up in office practice, he added. "I've been staggered by how much fatigue I've seen."

Enzalutamide reduces the plasma level of several types of medications, including fentanyl, warfarin, phenytoin, and omeprazole.

For both abiraterone and enzalutamide, men should wear a condom during any sexual activity if pregnancy is a concern, since either drug could pass to his partner and is contraindicated for pregnant women.

<<<

View more from the 2015 LUGPA Annual Meeting