E. David Crawford, MD, discussed issues with FDA standards for ADT agents and current treatment approaches to androgen deprivation in prostate cancer at the 2015 LUGPA Annual Meeting.
E. David Crawford, MD
Patients treated with hormone-based therapies for androgen-sensitive prostate cancer have better outcomes when they achieve testosterone levels <7 ng/dL—significantly lower than the 50 ng/dL that the FDA recognizes as a castration threshold, E. David Crawford, MD, said in a presentation at the 2015 Large Urology Group Practice Association (LUGPA) Annual Meeting.
“Prostate cancer is a hormonally dependent cancer and we need to understand that. The goal is to lower or block androgens, and the lower the better. Get the level as low as you can and keep it as low as possible,” said Crawford, who is head of Urologic Oncology at the University of Colorado. He cited studies showing a two-fold difference in risk of death between patients with testosterone levels<20 ng/dL and those with levels >50 ng/dL.
According to Crawford, the FDA still bases its standard on an old technique for measuring testosterone that cannot detect levels much lower than 50 ng/dL. Newer chemoluminescent and mass spectrometry techniques can measure as little as 0.1 ng/dL. Now that patients can be tested for such low levels of androgens, Crawford said mounting evidence supports a standard of <20 ng/dL.
The FDA also seems to apply a different standard to hormone therapies for prostate cancer than to other types of drugs, Crawford observed. “These drugs are letting us down,” he said. “Less than half the time do you keep testosterone in a range less than 20, and a quarter of the time it’s above 50. That would not fly with the FDA if it were some other kind of drug with that variation."
When the LHRH agonist leuprolide was approved for prostate cancer treatment in 1985, it was based on a single study comparing the drug with DES in a group with a total of 199 patients, and measuring survival rates at 1 year. “That would never ever happen today,” Crawford said.
The session at LUGPA examined and compared the abundance of current approaches to androgen deprivation, including estrogens (eg, diethylstilbestrol), bilateral orchiectomy, LHRH agonists (eg, leuprolide), and the GnRH antagonist degarelix (Firmagon). Crawford also discussed antiandrogens, such as flutamide and bicalutamide.
“If we had an antiandrogen that really worked, I do believe it would be the best way to treat,” he said. However, he cited a study showing that bicalutamide is less effective than bilateral orchiectomy for preventing the progression of cancer. The drug also has gynecomastia as a significant side effect.
Crawford added that the newer antiandrogen enzalutamide (Xtandi), approved by the FDA in 2012, has shown a survival advantage of almost 5 months over placebo when used after chemotherapy.
Bilateral orchiectomy has historically been considered the "gold standard" for starving prostate tumors of androgens, because it is a relatively quick and inexpensive outpatient procedure and it reduces testosterone more quickly than any drug can.
But Crawford disputes the assessment. Orchiectomy is extremely unpopular with patients. He observed that in one study, almost 90% choose an injection of LHRH agonist rather than the irreversible surgery, and he speculated that most meeting attendees probably have not done an orchiectomy in at least 6 months.
The procedure also has a broad spectrum of side effects, including negative sexual and vasomotor effects, metabolic and cardiovascular implications, and bone loss. It also does not eliminate all androgens, since some are produced by the adrenal glands and by the prostate tumor cells themselves, and these small amounts can be enough to support the continued growth of the cancer.
He cited one study showing that tissue concentrations of dihydrotestosterone after orchiectomy are 2 ng/g—lower than the levels of 5 ng/g for both BPH and cancer, but not that much lower than a normal level of 2.5 ng/g.
Most importantly, orchiectomy causes an increase in follicle-stimulating hormone (FSH), which in itself may play a role in cancer progression, as well as causing cardiovascular problems. Several studies by Crawford and others have shown that FSH stimulates the growth of prostate cancer cells in vitro.
The different pharmacological approaches to ADT are by no means equal in their ability to block androgen production, and their performance can be erratic, Crawford said. A 2007 study showed that one in four patients treated with LHRH agonists had testosterone levels >50 ng/dL during their therapy. Other common variations include testosterone surges or flares. And some patients don't respond at all.
Crawford urged attendees to monitor patients’ testosterone levels regularly while they are receiving LHRH agonists and be alert for inadequate response, because the performance of secondary therapies like steroids and antiandrogens may depend partly on how well the initial therapy works.
“When patients fail hormonal therapy, second-line therapy gives us a 30% response, and why is that?" he asked. “It's because they weren't suppressed to begin with, and if we did a better job of doing that, that wouldn't happen."