Prostate Cancer Notes and Notable – Dr. Judd W Moul: Part 1 – A Leading Clinician’s View on Zytiga® and Xtandi®

Drug Market Info presents Prostate Cancer Notes & Notable, an interview series with leading voices in the fight to cure Prostate Cancer. (For more data on Prostate Cancer, see the Drug Market Info Prostate Cancer Fact Sheet)

Today’s interview is with Judd W Moul, MD,  Director of the Duke Prostate Center, Professor of Surgery, Duke University School of Medicine and the James H. Semans, MD Professor of Surgery at the Duke Cancer Institute. Dr. Moul is an international authority on prostate cancer and outcomes/database research. His clinical interests include minimally invasive nerve-sparing radical prostatectomy, multidisciplinary management of prostate cancer, and clinical trials in prostate disease. He was director of the Center for Prostate Disease Research, a Congress-mandated research program of the Department of Defense. He received national acclaim for creating a prostate disease research database that houses information on more than 20,000 prostate cancer patients treated at nine collaborating institutions. In 2009, he was selected as a recipient of the “National Physician of the Year” award, presented by Castle Connolly, publisher of the America’s Top Doctors series.

Here are some Notes from Dr. Moul on Xtandti® (Medivation), Zytiga® (Johnson & Johnson)  and treating prostate cancer:

What do you think about Xtandi, the new drug from Astellas/Medivation? Could you have predicted that it would be approved three months early?

We have been hearing about this new drug now for the past 2-3 years. We were first introduced to it as “MDV-3100” and more recently by its new generic name, “enzalutamide.” What is brand new for me is the catchy trade name of “Xtandi.” I am very excited about this new oral antiandrogen because of its triple mechanism of action against the androgen receptor and its impressive survival advantage over placebo in castrate-resistant prostate cancers (CRPC) that have progressed after chemotherapy. I was not really too surprised when it was approved early because it showed impressive survival gains with an excellent safety profile.

Where will Xtandi fit into the treatment regimen for Prostate Cancer?

Enzalutamide will initially be used in men who have castrate-resistant prostate cancer (CRPC) and who have progressed after docetaxel-based chemotherapy. In other words, these are men who have metastatic (spread) prostate cancer who have stopped responding to traditional hormonal medications- the LHRH agonists/antagonists and the traditional oral antiandrogens, and also after docetaxel-based chemotherapy. The most common clinical scenario will be those men who have a rising PSA level and or progression of their metastatic disease while being managed with traditional hormones, such as leuprolide acetate and docetaxel chemotherapy. At this point, the managing physician would continue the leuprolide-type LHRH agent but discontinue other cancer drugs, including the chemotherapy, and start the man on Xtandi.

What about Zytiga? Is it effective for patients where cancer has metastasized (with few or no symptoms) following androgen-deprivation therapy? Is this a difficult patient group to treat?

Zytiga, or abiraterone, is another novel hormonal medication that was FDA-approved in April 2011 for men with CRPC. It is also effective and showed a significant survival benefit in men who had stopped responding to docetaxel-based chemotherapy. We now have three FDA-approved new medications in the “Post-docetaxel space” in CRPC: cabazitaxel (Jevtana®); abiraterone (Zytiga) and now enzalutamide (Xtandi). Jevtana (25 mg M-squared IV given every three weeks with low-dose oral steroids) is a taxane systemic chemotherapy that was approved in June 2010 and was the first novel drug to show a survival benefit in post docetaxel CRPC. The median survival benefit was about 3 months and it received accelerated FDA approval due to it being the first agent to show improved survival in this group of patients.

Zytiga is an oral agent taken at a dose of 1000 mg daily (four 250 mg tablets taken once daily along with low-dose oral prednisone 5 mg twice daily). The biggest challenge now will be to learn how to properly sequence these three novel agents for maximal patient benefit. Furthermore, both Zytiga and Xtandi are both effective in men who are pre-chemotherapy CRPC and are both likely to be approved in the next year or so in the pre-chemo space. The clinical trials of all three of these agents were done independent of the other two so we still have to learn how to use these drugs together and in the best order for our patients.

What have you heard from patients about Zytiga? What about side effects or any other patient-related issues?

Zytiga is well-tolerated; however, does have to be given with low-dose prednisone. It may cause hypokalemia (low serum potassium levels) so doctors need to measure a serum potassium level before starting the drug and need to monitor levels periodically. It can also cause fluid retention and hypertension so oncologists and urologists need to be aware and monitor appropriately. In the post-docetaxel setting where it is currently FDA-approved, the low-dose steroids are not generally an issue and patients are being monitored by oncologists and their staff pretty often. However, when Zytiga becomes FDA-approved in the pre-chemotherapy setting where men are generally healthier and may not be monitored as often, doctors will need to be a little more vigilant with monitoring patients on Zytiga.

Also, in the pre-chemotherapy setting, patients are generally under the care of urologists and not oncologists. Among urologists, we are working hard to further train a subset of urologists to use these new agents who will be very comfortable managing men in this new era. As far as patients, what I have heard is that virtually all patients are excited about the new options where we have more to offer them and the prospects of making advanced prostate cancer more and more of a chronic disease.

With all of these new treatment options, how will doctors decide which drugs to use and where?

This is the key question to our field now that we have four new agents available in the last several years for use in advanced prostate cancer. If we follow the current (Sept 2012) FDA-approvals and use these drugs fully on label, then the sequence might look like this:

1. Provenge®; 2. Docetaxel; 3. Zytiga or Jevtana or Xtandi depending on the physician and patient preference. Also, denosumab (Xgeva®), a new RANK-Ligand inhibitor given at 120 mg subcutaneously every month, is also FDA-approved to prevent skeletal events in men with advanced prostate cancer. It can be used as soon as a man is diagnosed with bony-metastatic prostate cancer or can be reserved for those with CRPC at a similar time as the patient is eligible for Provenge.