On March 4, 2014 I wrote a post “Castrate Resistant Prostate Cancer- What to Do Next” (www.advancedprostatecancer.net/?p=4425). The basic theme of the post was about how difficult it is to know how to sequence the new drugs we have to treat advanced prostate cancer (metastatic castrate resistant prostate cancer aka mCRPC).
In the post I said “There is a small trial that has shown that in many cases Xtandi will still be effective after the failure of Zytiga. I am not aware of a trial with results that has shown the efficacy of Zytiga after Xtandi (not to say that it won’t be effective).” Since I wrote that I have become aware of a very similar small trial that has demonstrated that that after failure of enzalutamide (Xtandi) abiraterone (Zytiga) will still work for some men.
In both cases there is some cross resistance, but we simply do not know the actual extent of the cross resistance nor which of these drugs might create more resistance.
Bottom line is that as of this moment we do not know which of these drugs would serve as the best first drug. There is a lot of on going research examining sequencing and combining therapies.
Until we have more data it is like the wildwest, to some extent we will have to shoot from the hip. However, we should rely on our doctors for guidance when making these decisions. This is one of the many reasons that we must make sure that our treating physicians are on the cutting edge and know as much as possible about advanced prostate cancer. This means that they specialize in treating men with advanced prostate cancer and not be general oncologists treating all cancers.
Ann Oncol. 2013 Jul;24(7):1802-7. doi: 10.1093/annonc/mdt138. Epub 2013 Apr 12.
Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide.
Noonan KL1, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN.
Joel T Nowak, M.A., M.S.W.
Satraplatin is an oral platinum drug that is believed to bind the DNA of the cancer cell, which then prevents the cancer from being able to reproduce. Satraplatin had been tested in a phase III trial in men with metastatic castrate-resistant prostate cancer (mCRPC) who have failed chemotherapy with docetaxel. It failed because it did not show a median survival benefit and was not approved by the FDA.
Despite the lack of a demonstrable survival advantage additional analysis of the data showed Satraplatin was a drug that did show objective evidence that it works and inhibits tumor growth, but did not work in enough men to change the statistical balance demonstrating a survival advantage. The question remains as to whether it’s possible to identify those men who will respond to satraplatin?
In a biomarker development trial being conducted by Mathew D. Galsky, MD, Associate Professor of Medicine, Hematology and Medical Oncology and Assistant Professor of Urology at The Mount Sinai Hospital, New York, about half of the subject men saw benefit with satraplatin, consistent with the original phase III results. Galsky is now looking at tumor samples (from biopsies) to see if tissue biomarkers can be identified to allow us to know which men would benefit from the drug.
This biomarker study is a great example of how we will be developing personalized medicine, even from data generated by what traditional science would call a failed clinical trial. In this particular study if we identify biomarkers we will then have to re-do the clinical phase 3 trial sorting out and including only those men having the biomarker. Good science and follow through actions we might be able to raise phoenixes from the ash.
This type of study would also greatly benefit all the drugs we currently use to treat prostate cancer, even those that have shown a statistical survival benefit and been FDA approved. None of our drugs work on every person; in reality many of them will not do anything to help as much as 40% of us. It would be great for us to be able to look at out own biomarkers and know if a treatment would benefit us without our having to spend the absorbent cost of a drug which will not work for us while also allowing our cancer to progress.
Joel T. Nowak, M.A., M.S.W.
Confusion, confusion and more confusion, that is how I would describe the current decision making process for a man with prostate cancer that has become newly castrate resistant. Just a few years ago the decision tree was clear, castrate resistant, immediately on to chemotherapy with docetaxel.
Today, in this treatment space, we have a number of new drugs available that are FDA approved. These include sipuleucel-T (Provenge) and abiraterone (Zytiga) with prednisone. Presumably in the next 3 to 4 months we will also have another new drug, enzalutamide (Xtandi) in this same treatment space.
Knowing which treatment to take, in what order and or in combination is the biggest question facing us when our prostate cancer becomes castrate resistant.
It’s commonly agreed by many physicians at the first treatment should be Provenge. Provenge has shown the ability to extend a man’s life, however it does not limit the rise of PSA or disease progression. Subset analysis of clinical trial data clearly demonstrates that the men who will receive the most benefit from Provenge are men with low PSA levels (most likely newly castrate resistant). It seems that the cut off for the efficacy of Provenge is around 22 ng/ml, so it makes sense to use Provenge first while the PSA level is underneath this threshold and the disease has not had major progression.
After the administration of Provenge the decisions become less clear. There has to be a decision between using Xtandi or Zytiga or perhaps both of these drugs in combination. Current knowledge from clinical trials does not provide an answer, so we need to fly by the seat of our pants.
Many would argue that it makes the most sense to first use Xtandi because Zytiga with a steroid comes with a list of side effects. After failure of Xtandi one could move on to Zytiga (with a steroid). However, to date there has not been any clinical trials that has demonstrated this order to be superior.
There is a small trial that has shown that in many cases Xtandi will still be effective after the failure of Zytiga. I am not aware of a trial with results that has shown the efficacy of Zytiga after Xtandi (not to say that it won’t be effective).
A little out of the ordinary, but something I find interesting would be using Provenge and then immediately entering into the clinical trial for ProstVac. Prostvac is the most promising new immunotherapy on the horizon and I wonder what the one, two punch of Provenge and Prostvac could actually do to bet down advanced prostate cancer. (Caution- Prostvac is still in clinical trials and not FDA approved. Additionally, there are no trials looking at this combination of treatments, Provenge then Prostvac).
Becoming castrate resistance and not moving on immediately to chemotherapy can be frustrating. However the fact that we have these questions bodes well for us and it offers us serious hope for both today and tomorrow. Remember that just three or four years ago we had no choices. Having these choices without clear direction adds strain and anxiety, but it also offers options, new directions and an extended life with a decent quality.
There are currently a number of studies that are designed to give us better direction as to the best order of these treatments. Until then we must rely on the instincts and the experience of our doctors.
Joel T Nowak, M.A., M.S.W.
It has been announced by the International Strategic Cancer Alliance that a Dutch university that intends to launch global trials has purchased the Combidex technology.
Combidex is a scan contrast that periodically gets discussed among prostate cancer survivors, but it has not been available for a few years. It is an injectable nanoparticle fluid (contrast) used with magnetic resonance imaging (MRI) that can visualize cancer metastases with pinpoint accuracy in lymph nodes as small as 2 – 3 millimeters, compared to conventional CT imaging, which can only visualize malignant nodes that are larger than 8 millimeters.
If it proves to meet its hype it will improve cancer diagnostic imaging.
The new owner of the technology is Radboud University Nijmegan Medical Center (RUNMC), a part of Stichting Katholieke Universiteit, a non-profit foundation in The Netherlands. Under the direction of radiologist Jelle Barenntsz, they will continue research and development of Combidex. They have indicated they intend to conduct global clinical trials advancing towards regulatory application and its commercialization.
Given the many other new contrasts under development the question is will there be room for Combidex?
Joel T. Nowak, M.A., M.S.W.
The commonly used serum (blood) marker for inflammation is C-reactive protein (CRP). It is believed that CRP has a prognostic impact for men with metastatic prostate cancer (MPC) (advanced prostate cancer). The researchers conducted a meta-analysis to quantitate its prognostic impact.
They conducted asystematic review to identify publications and presentations exploring the association of baseline serum CRP and overall survival (OS) in MPC, both castration-sensitive and castration-resistant.
After performing some statistical manipulations of the data they determined that six studies comprising 659 evaluable patients were eligible. The first authors of the six studies were: Prins (N=119), Pond (N=112), Ito (N=80), Nakashima (N=126), Beer (N=160), and McArdle (N=62). The Nakashima and McArdle studies evaluated castration-sensitive men, while the remaining four studies evaluated castration-resistant men receiving docetaxel-based chemotherapy.
The primary endpoint was overall survival (OS) except the McArdle study, which used cancer specific survival.
Men with higher CRP (more inflammation) had significantly worse OS than those with lower CRP (HR = 1.42, P<0.001, 95% CI: 1.17 to 1.73; I2 = 72.6%, p = 0.003). In trials of castration-sensitive men receiving hormonal therapy, high CRP yielded a HR = 1.92 (P=0.005, 95% CI: 1.22 to 3.03; I2 = 0). In castration-resistant men receiving chemotherapy, high CRP yielded HR=1.35 (p=0.003, 95% CI: 1.11 to 1.65; I2 = 79%), P for subgroup difference=0.20.
The meta-analysis suggests a strong prognostic impact for CRP on OS in men with both castration-sensitive and castration-resistant prostate cancer. Prospective validation is justified, given the affordability, ready availability and large dynamic range of CRP.
What might we do with this information? This study concludes that men with higher levels of inflammation have a worse prognostic outlook. Can lowering a man’s CRP improve their OS? Until this type of study is conducted we cannot answer this question, but given our ability to control inflammation it is an issue that should be discussed with your doctor.
Inflammation can be controlled by drugs and by diet and exercise. Clearly diet and exercise is a thing any of us should be able to control. What is a healthy, anti-inflammatory diet? There are many different takes on this, but The anti-inflammatory diet is “probably very close to the Mediterranean diet ” says Christopher Cannon, MD, associate professor of medicine at Harvard Medical School and a cardiologist at Brigham and Women’s Hospital, Boston.
J Clin Oncol 32, 2014 (suppl 4; abstr 43); Gurudatta Naik, Charity Morgan, Pedro Filipe Simoes da Rocha, Arnoud J. Templeton, Gregory Russell Pond, Guru Sonpavde; University of Alabama at Birmingham, Birmingham, AL; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada; McMaster University, Hamilton, ON, Canada; University of Alabama, Birmingham (UAB) Comprehensive Cancer Center, Birmingham, AL
Joel T. Nowak, M.A., M.S.W.