Prostate Cancer Notes and Notable – Dr. Judd W Moul: Part 2 – Sequencing and Prostate Cancer Treatment

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 we present Part 2 of our interview 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. (Click here for Part 1 of the interview, focusing on new prostate cancer drugs Zytiga and Xtandi.) 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 “Sequencing” and treating prostate cancer:

How do you currently select which therapy to use for men with prostate cancer who are castrate-resistant, but not yet symptomatic for metastatic disease?

There is only one FDA-approved new agent for this population and it is Provenge® (sipuleucel-T) immunotherapy. Provenge is specifically approved for asymptomatic or minimally symptomatic metastatic CRPC. It is best used for men who have mets (metastases) but are not yet on narcotics for cancer-related pain and who have early CRPC. New data suggest it is best for men who have a lower PSA level, such as less than about 25 ng/ml. At the Duke Cancer Institute (DCI), we have used Provenge extensively and like to sequence it as the first novel treatment for CRPC before chemotherapy and early in the course of metastatic CRPC.

Zytiga® is now being reviewed as a treatment for prostate cancer in patients who have not received chemotherapy. The FDA should finish in mid-December. What are your thoughts – will it get approved? Does it improve survival?

I certainly do not want to speculate on FDA decisions. However, Zytiga is clearly very active in the setting of CRPC prior to docetaxel-based chemotherapy. The drug resulted in an improvement in progression-free survival and significant delay to chemotherapy compared to placebo. Survival was also improved, but just missed being statistically significant at the current analysis. With regard to survival, the current P-value for significance was just higher than the standard benchmark of P= 0.05. As more patients are followed for survival, this result may become statistically significant. However, with more novel agents being used in these patients, this may be part of the reason that the survival endpoint was not completely met.

From your experience, would most prostate cancer patients rather take Zytiga than go on chemotherapy?

I think the message to patients is that all of these new agents are important and I do not like to pit one drug against another. Some patients will prefer to start an oral therapy before further chemotherapy. However, currently Zytiga is only FDA approved for men who have progressed on docetaxel-based chemotherapy and some men may want to march on with further chemotherapy and would go on to Jevtana®. Other men may desire a break from chemotherapy and will prefer Zytiga before moving on to Jevtana. It is up to us as prostate cancer doctors to educate our patients about all the new options and to prepare and educate patients that they may need all these new drugs given in a sequential fashion.

What about Provenge, where do you think it fits?

As noted above, Provenge is a novel cellular immunotherapy custom-made for each patient and can be administered over about 4 weeks with three separate leukophoresis procedures followed several days later by re-infusion of activated product. In two separate phase III clinical trials, the survival benefit was 4.1 to 4.5 months compared to a placebo control group. However, two-thirds of the control patients received a frozen cellular immunotherapy similar to Provenge at the time they progressed on placebo. Recent secondary analyses have suggested a greater survival benefit for men who had lower PSA values (less than about 25 ng/ml) and perhaps that a comparison of Provenge to true placebo patients may result in a greater survival benefit than the reported survival benefit of 4.1 months. I think Provenge fits in the earliest phase of metastatic CRPC while patients have a robust immune system and it should be given ideally at least 3-6 months before the patient is expected to need chemotherapy or steroids.

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.

There is a lot of talk about “sequencing.” What does it mean for prostate cancer treatment?

As noted in some of the earlier questions, it is using the new agents in the correct order for the individual patient. We are very excited that the “toolbox” has more tools to help us treat our patients with advanced prostate cancer. However, we are not certain which order to use all the new riches at our disposal.

What are your patients saying about all the new drugs? What is still needed?

My patients have renewed optimism about their prospects even when they develop metastatic prostate cancer. However, they are also concerned that the government via the US Preventative Services Task Force (USPSTF) has recommended that doctors stop using the PSA test to screen for prostate cancer. If we truly go back to the “Pre-PSA Era” we will go back to a time when 20-25% of men present initially with metastatic prostate cancer. Currently, in the PSA-Era this had fallen to only about 2%. We may see more patients who are candidates for these new agents because we are no longer picking up cancer early.

In my opinion, we still need to look for the disease earlier especially in younger men where a diagnosis of metastatic prostate cancer is still a death sentence despite all the new drugs. However, we do need to do a better job to fine tune testing in older men to avoid overtreatment. We also need better disease markers for early and advanced disease – PSA is good, but we need even better disease markers. We also need a better way to image inside the prostate so we can better define early stage tumors for individual patients.