Several new drugs have become available for treating advanced prostate cancer in the past year and a half. E. David Crawford, MD, head of urologic oncology at University of Colorado (UC) Hospital and an investigator at the UC Cancer Center, both in Aurora, and UC colleague Thomas W. Flaig, MD, recently published a review of these agents. Dr. Crawford talks to Renal & Urology News about the possible ways in which these drugs might be used.
Why did you undertake this review of new agents for the treatment of prostate cancer? (Oncology [Williston Park] 2012;26:70-77)?
Dr. Crawford: For the past few decades, there really hasn’t been a significant amount of progress in advanced prostate cancer. The last landmark thing—the positive studies with docetaxel [Taxotere, from sanofi-aventis] in castrate-resistant prostate cancer—was almost 10 years ago.
But in the past 18 months four new drugs, all with different mechanisms of action, have been approved, and we have three more in the wings. This has created a lot of excitement in how these things are going to fall into place, how they’re going to be sequenced.
I’m on the editorial board of Oncology, and when I suggested this as a hot topic, they said, “Okay, write it!” So Tom Flaig and I did. It was a lot of work, but a lot of it was just our opinion. Maybe other people don’t agree with our outlook for future sequencing of therapy for advanced prostate cancer.
Why did we have an 8.5-year lull after docetaxel, and then this flurry of activity in the past 18 months?
Dr. Crawford: The interest in docetaxel sparked a lot of trials of combinations of docetaxel and novel new agents. Unfortunately, none of those trials turned out a super-winner. Therefore, there was a hiatus of a number of years where these doublets with docetaxel were evaluated.
Parallel to that were discoveries that this cancer is androgen-dependent. Everybody kind of thought, “Well, it’s androgen-independent or hormone-refractory.” Those two terms were replaced with “castrate-resistant,” which means that it’s resistant, but you can overcome that resistance by further lowering testosterone. That led to [the use of] ketoconazole over a decade ago, which worked a little bit.
But what really moved things forward were the studies with abiraterone [Zytiga, Janssen], an oral inhibitor of CYP17, which lowered testosterone more, and you got a response, and MDV3100 [from Medivation], which is a new-generation anti-androgen, and the immunotherapy [sipuleucel-T, or Provenge, from Dendreon]. So the seeds were planted, and they grew and blossomed all at the same time.
It used to be that for advanced disease we had hormone therapy, and if that failed, we tried chemotherapy. [This approach] never showed anything positive. I was chairman of the genitourinary cancer committee at Southwest Oncology Group for 28 years and we studied every drug known to mankind in advanced refractory prostate cancer, and nothing really worked.
Then the big trial with docetaxel showed a modest survival benefit of two to three months. That was the first step forward, and it generated a lot of excitement and the development of these other drugs.
So what new drugs do urologic oncologists have at their disposal?
Dr. Crawford: We have sipuleucel-T, a novel immunotherapeutic agent—the only approved immunotherapeutic agent for cancer. It results in a survival benefit of four-plus months. We have a new bone agent, denosumab [Prolia and Xgeva, from Amgen], an inhibitor of the RANKL protein. We have abiraterone, which is new and has a novel mechanism of action in castrate-resistant prostate cancer. A recent study of abiraterone in the pre-chemotherapy setting was apparently positive. We have cabazitaxel [Jevtana, from sanofi-aventis], which is another chemotherapeutic agent.*
The question is, what do we do with these drugs? So Tom Flaig and I reviewed those agents—what the studies were—and we included a figure showing where we were in 2009, where we are in 2012, and then we discussed where we might be beyond that.