New Metastatic Prostate Cancer? First, Take a Deep BREATH

A new diagnosis of metastatic prostate cancer is life-altering.  Deciding on the treatment used to be straightforward but it’s not anymore. After addressing this issue with patients for many years, and staying abreast of the latest developments, I describe an approach to starting treatment in five questions for both the patient and the physician. These may affect the trajectory of the disease, the choice of treatment and hopefully, improve peace of mind. And since the easiest path to learning retention comes viamnemonic devices and acronyms – consider the first step that it is all about first taking a deep B.R.E.A.T.H:

  1. What’s the Biology of the disease?
Prostate cancer has many biological faces.

Consider this, a patient can arrive at having metastatic prostate cancer through one of two paths. One is after experiencing a rising PSA after radical prostatectomy or radiation therapy and eventually developing metastases.  The other is when metastases are discovered at the time of initial diagnosis, without any prior treatment for the disease. If this is recurrent disease and the patient has already had local therapy, it is possible this could be slower moving than if it is a brand-new diagnosis. You would think that this would be an easy thing to know but some methodological challenges make this a tough call.

If it is newly diagnosed, we don’t really have an idea if this is a slow-growing disease that has been in there a long time or whether it is a newly formed rapid process. We have been analyzing some data along these lines and I first published on this over ten years ago. In that paper, we found that the tumors that initially presented as metastatic disease are more likely to be of a higher Gleason grade. This suggests that when a patient presents with de novo metastatic disease the disease biology may be such that the tumor formed and spread to radiographically evident metastatic sites early. The patient with a relapse after surgery who develops radiographically evident metastases actually had non- radiographically evident metastases all along, they were just slow growing and took a while to show up on scans.

Bear this in mind when reviewing clinical trial data.  The CHAARTED study, for example, included both patients with de novo metastatic disease and those who had previously undergone local therapy ( about 70% had no prior therapy, 10% radiation, 20% prostatectomy) whereas in the LATITUDE study ALL patients had de novo metastatic disease and were ineligible for the study if they had undergone prior radiation or prostatectomy. In light of the fact that the survival curves are almost identical, it may be a hint that perhaps ADT plus Abi is a bit better than ADT plus docetaxel, but we really don’t know that for sure.

But if we are really going to talk about the biology of the disease we need to determine what are the molecular differences in terms of the key drivers of aggressive prostate cancer and how common, or uncommon, they are in the recurrent vs de novo metastatic patients. What are the proportions in each with aberrations in p53, Rb, TMPRSS-Erg, BRCA2, MSH2 etc? All of these are currently being studied. So, one day we’ll know. For now, however, it may be worth gathering the data by sending biopsy material for next-generation sequencing. Gather the data.

  1. What can we learn from the  Relatives?
More than ever before, knowing the patient’s family history is important. Although it may not lead to more cures yet, it is a good way to begin the planning of the long arc of treatment that may be ahead. Knowing that a new patient has a germline BRCA2 mutation, for example, would alter how I sequence my therapies, in particular, I would want to make sure that my treatment didn’t render them ineligible for eventual treatment on a Parp inhibitor trial. Further, over time, we are going to see studies emerge that “front load” aggressive therapies like chemotherapy targeted at a particular patient population. At my center, the University of Minnesota in the Twin cities, we are piloting a study that will utilize carboplatin plus cabazitaxel up front in patients with high volume disease and we are hoping to capture some patients with DNA repair alterations who may benefit from the early addition of Carboplatin.

The key point is to take a family history. If there is a strong history of prostate, ovarian, pancreatic or breast cancer, consider germline genetic testing and, perhaps more importantly, bring genetics counselors onto the case.

And while we’re at it, we also might want to think more deeply about the NON-cancer family history. Is cardiovascular disease a big risk? Lipids? Stroke? etc. knowing all this may be beneficial in counseling the patient about his general health while on ADT.

  1. What is the Extent of disease?
Several years ago, we didn’t parse out the number of metastases very much because we didn’t think it really mattered.  While it is intuitive that the number of metastasis corresponds with a more aggressive disease, we now have data on this point. This has been written about extensively with regard to the CHAARTED and STAMPEDE Trial studies, where the addition of docetaxel appears to be quite beneficial for those with extensive disease but not so much for those with less extensive disease. The line in the sand, in that case, was four metastases.

But the other layer of complexity that is emerging rides on the hope that we may be able to cure a small number of individuals who harbor oligometastatic disease. This new hope, which has yet to be proven, rides on the development of two new technologies – better imaging and better pinpoint radiation. The new imaging, PSMA and Axumin PET, are the results of molecular tracers that can highlight specifically where prostate cancer metastases.

The ‘new’ radiation is stereotactic body radiotherapy (SBRT), which allows more directed radiation to be delivered with the advantage of not having to create a ‘field’ and thus, it is hoped, the treatment can be focused on the metastases, and not on the normal tissues.

This is not available everywhere and, most importantly, is not a proven therapy. Those of us who design clinical trials for a living understand that to prove that radiation of oligometastatic disease would take many years and require a control arm. As a result, this may be one of those rare technologies that get adopted for use without an adequate ‘put up or shut up’ phase III trial.  Since many men with oligometastatic disease will live a decade or more, designing and completing a clinical trial in this space will take upwards of 15 years. Some have been proposed, and it is being discussed, but there is nothing that I know of in the pipeline yet.

  1. Should the patient be treated with Abiraterone?
The LATITUDE and CHAARTED studies, mentioned before, evaluated and proved that adding one or the other to ADT improved outcome. But which one? We may never really know that answer and it might, in fact, be a toss-up, or even that doing both is best, we just don’t know yet.

Abiraterone has the advantage of being orally available and having a more agreeable safety profile than its counterpart docetaxel (I use the tradename “Taxotere” below, for the purposes of acronym integrity).

When treating a patient in the hormone-sensitive metastatic setting it is reasonable to ask if the abiraterone needs to be continued indefinitely or whether the benefit is in the early phases of the treatment only. I have written about this elsewhere on UroToday.com.

Personally, I tell patients we will make these decisions on a year by year basis. If a patient is treated with ADT plus Abiraterone and, a year later, has a PSA of zero, there is a reasonable chance he will respond for the next year, and the next. It’s at this time that the potential for toxicity with hypertension and potassium abnormalities may become a worry. So, I think its reasonable to consider decreasing the dose or even stopping it altogether in the exceptional responders. If the psa blips up, we could restart. We don’t really know what to do in these circumstances. Treatment with Abiraterone as per Latitude can be a long-term process, allowing for reasonable discussion of whether docetaxel is a reasonable first choice.

  1. Should the patient be treated with Taxotere?
When the CHAARTED and STAMPEDE data was first released it made a compelling case that all patients with newly diagnosed metastatic disease should get docetaxel treatment. It upended practice patterns in the US a bit too because now it meant that all patients should see a medical oncologist at the time of diagnosis of metastatic disease – the standard for almost all other solid tumors besides prostate cancer. But, this was survival data so needed to be recognized or the patient was not receiving the standard of care.

The case to give patient Taxotere is simple: Improved survival comes with only 6 doses of a generic and reasonably well tolerated therapy. After the sixth cycle, the patient can remain on ADT alone without worry of monitoring, toxicity or cost of abiraterone.

So, the pendulum may swing back for some clinicians and patients. Recognizing the short duration, long benefit and low cost of docetaxel, it may be a better choice.

  1. Don’t forget General Health!
Finally, it is important to remember that many patients with metastatic hormone-sensitive prostate cancer are going to do very well on treatment and are going to have cancer control that lasts for years. Thus, it is important to talk to them early about the metabolic changes that come from ADT (Insulin resistance and diabetes, osteoporosis, weight gain, and cardiovascular complications)


I try to emphasize this fact when sitting down with a newly diagnosed patient:
If they don’t exercise, they should start.
If they already do, they should continue
Resistance work with weights is important to maintain muscle mass and stimulate metabolism
Working ‘against gravity’ is also important to maintain bone strength.

Check lipids, follow blood pressure, do a baseline bone density scan. If the patient doesn’t already have a primary care doctor, they should get one. Many patients with metastatic prostate cancer will die of other causes. The treatment for the prostate cancer may increase the risk of cardiovascular disease and thus, we must be mindful of it.

Written by: Charles J. Ryan, MD
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