At major medical meetings like the recent AUA and ASCO annual meetings (the latter wrapping up today in Chicago), what goes on in the conversations in the corridors and in private meetings is often more important and interesting than what is being presented from the podium or talked about at poster sessions.
When it comes to prostate cancer, one of the really key issues taxing the medical oncology community at ASCO over the past few days has been, “How do we need to start thinking about the future treatment of advanced prostate cancer?”
Historically, i.e., until the approval of docetaxel (Taxotere) + prednisone for the treatment of hormone-refractory prostate cancer in May 2004, patients with advanced and metastatic prostate cancer really had only two meaningful treatment options: surgical castration (orchiectomy) or drug therapy designed to have a similar effect (with LHRH agonists like leuprolide acetate and antiandrogens like bicalutamide). To all intents and purposes, before the approval of docetaxel, there really was very little that a medical oncologist could do to help a patient with progressive prostate cancer, and the number of medical oncologists doing clinical research in this field had been small. The only drug approved for the treatment of men with hormone-refractory disease was mitoxantrone — which was known to have no impact on a patient’s overall survival.
With the approval of docetaxel has come an explosion in the number of compounds being tested for the treatment of advanced forms of prostate cancer, and we don’t plan to even try to offer you a complete list. It would be huge. However, here are the products that have either been approved in the USA or look as though they may have a good chance of being approved for the treatment of late-stage prostate cancer in the near future:
- Docetaxel (Taxotere) was approved 6 years ago for the treatment of men with hormone-refractory prostate cancer. It is a specific type of chemotherapy, normally administered in combination with a steroid (e.g., prednisone), and (on average) it offers such patients a couple of months of additional survival compared to a placebo or sugar pill. Patients taking docetaxel usually remain on hormone therapy. A small percentage of men who receive docetaxel chemotherapy may have a very extended survival benefit compared to the average.
- Degarelix (Firmagon) is a second-generation LHRH antagonist that was approved about 18 months ago. The easiest way to think about degarelix is to appreciate that it works like a combination of an LHRH agonist and an antiandrogen — so it offers combined androgen deprivation in a single molecule. This means that there is no hormonal “flare reaction” associated with treatment, and degarelix is much more effective than traditional hormonal therapies at lowering testosterone levels to castrate levels. What we don’t know (yet) is whether treatment with degarelix has any impact on the long-term survival of patients with prostate cancer.
- Sipuleucel-T (Provenge) was approved just a few months ago for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant (hormone-refractory) prostate cancer. As with docetaxel, to date, these men have all continued on hormone therapy while being treated with sipuleucel-T. Sipuleucel-T is the very first autologous cellular immunotherapy ever approved for the treatment of cancer. On average it offers patients about 4 months of additional survival compared to a placebo, but over time we are again likely to see that a small percentage of men have a very extended survival benefit from this type of therapy.
- Cabazitaxel is a “second generation” taxane (i.e., a drug like docetaxel) which has yet to be approved but which has already shown that it can extend the survival of men who have relapsed after treatment with docetaxel. Like docetaxel, it is given in combination with a steroid. On average it extended survival by 2.4 months compared to mitoxantrone + prednisone. We expect that cabazitaxel will gain FDA approval for the treatment of prostate cancer within the next 12 months.
- Abiraterone acetate is the first of a new type of hormone therapies that acts more like ketoconazole than like an antiandrogen. It is currently being tested in two, major, Phase III clinical trials, and both trials are fully enrolled. The first trial is in men who had progressed after treatment with docetaxel + prednisone, and the results of this trial are to be expected within the next 12 months. The second trial is in men who had progressed after standard hormonal therapy but who had not received either ketoconazole or chemotherapy to treat their prostate cancer. The results of this second trial might be available in late 2011, but 2012 seems more likely.
- MDV 3100 is another drug that has similarities to abiraterone acetate. It is clearly very active in advanced prostate cancer (based on available Phase II trial data), and patients can currently enroll in a multi-center, randomized Phase III clinical trial if they have already been treated with a docetaxel-based chemotherapy regimen and have progressive disease after such treatment.
- Dasatinib (Sprycel) is a drug that has already been approved to treat two types of leukemia. There is a large, ongoing, Phase III clinical trial of docetaxel + prednisone with and without dasatinib in patients with hormone-refractory (castration-resistant) prostate cancer who have had no other form of pure chemotherapy. The intent is to see whether the addition of dasatinib to docetaxel will improve long-term patient survival.
- As we mentioned in a post the other day, ipilimumab is potentially the first monoclonal antibody that may get approved for the treatment of hormone-refractory prostate cancer. One major Phase III clinical trial has already started in patients who have progressed after chemotherapy and another Phase III trial will be starting soon to test the effectiveness and safety of ipilimumab in patients who are asymptomatic or minimally symptomatic and who have not received either immunotherapy or chemotherapy. A recent trial has shown that ipilimumab was able to extend the survival of patients with late stage malignant melanoma (a form of metastatic cancer that is extraordinarily difficult to treat).
- Atrasentan (Xinlay) — an endothelin receptor antagonist — is another agent that is currently being tested in combination with docetaxel. A large, multi-center, Phase III clinical trial is now fully enrolled and is testing docetaxel + prednisone with and without atrasentan in men with metastatic, hormone-refractory disease who haven’t received chemotherapy before.
- ZD4054 (also now known as zibotentan) is another endothelin receptor antagonist that is also being tested. In this case, the Phase III trials are being carried out in patients with non-metastatic hormone refractory prostate cancer as well as (separately) in men with metastatic disease. The trial in the men with metastatic disease is already fully enrolled.
- OGX-011 (also known now as custirsen) is a very different type of drug (an “antisense” agent) that is again being tested in a Phase III clinical trial in combination with docetaxel. This trial opened to enrollment only in March this year. Patients are randomized to receive docetaxel + prednisone with or without OGX-011. The trial can include patients with metastatic hormone-refractory prostate cancer who have never received chemotherapy or patients what have received not more than one complete course of chemotherapy.
- The VENICE trial is fully enrolled and has been testing the effectiveness and safety of docetaxel + prednisone with and without aflibercept in patients with metastatic, hormone-refractory prostate cancer who had received no prior chemotherapy.
- Lenalidomide (Revlimid) is another approved drug, currently used to treat certain types of blood cancers, that is being tested in a Phase III clinical trial. Once again, this is a trial of docetaxel + prednisone with and without lenalidomide designed to see if the addition of lenalidomide to docetaxel-based chemotherapy can extend long-term survival of patients with metastatic, hormone-refractory disease.
We could easily see as many as 10 new drugs approved for the treatment of castration-resistant prostate cancer between now and the end of 2013. Several of the drugs mentioned above are being tested in combination with docetaxel. However, the very real questions that are starting to tax the minds of the medical oncology research community (and of practicing medical oncologists) are:
- What is the right order in which to think about using these drugs in patients with progressive disease?
- Which of these drugs need to be given in combination with hormone therapy?
- Which of these drugs should we think about combining with each other?
- Should some of these drugs be given before we even think about standard, traditional hormone therapy?
From a time, not so long ago, when we had almost nothing available to help patients with castration-resistant (hormone-refractory) disease, we are suddenly being faced with a potentially overwhelming series of clinical possibilities. From a time when you could fit all of the medical oncologists who conducted clinical trials in prostate cancer into a very small room for an advisory board meeting, there is now a plethora of young investigators starting to build careers in this field of research.
Many of the corridor conversations at both the AUA and ASCO — but particularly at ASCO — revolved around the excitement about all these opportunities. So we offer you a paradigm for comparison. Twenty years ago there was only one drug known to have any significant impact on the treatment of multiple myeloma (a type of blood cancer), and people diagnosed with this disorder had an average lifespan of about 3 years from diagnosis. Today, there are men and women around the world who have been living with myeloma for 20 or more years — an unheard of feat at the time they were diagnosed. At the time of approval of Taxotere, the expected survival of a man with metastatic, castration-resistant prostate cancer was about 18 months to 3 years. But perhaps some of the men diagnosed with castration-resistant prostate cancer today will similarly still be living in 20 years time! That is something to get excited about.