We note that Pfizer and Astellas have recently modified the protocols for two large, international, randomized, Phase III clinical trials to see if they can get earlier results that might affect the potential for use of enzalutamide (Xtandi) in some groups of men with hormone-sensitive prostate cancer (HSPC). To get the details, please see here or here.
The two trials are these ones:
- The ARCHES trial, which is designed to test whether men with metastatic HSPC might respond better to androgen deprivation therapy (ADT) + a placebo or to ADT + enzalutamide, and has already enrolled about 1,150 patients
- The EMBARK trial, which is designed to test which of three possible treatment options works best for men with high-risk, non-metastatic HSPC — ADT (with leuprolide alone), enzalutamide alone, or ADT (with leuprolide) + enzalutamide, and has already enrolled about 1,860 patients
Note that in the ARCHES trial, “ADT” includes men treated with either a bilateral orchiectomy or a luteinizing hormone-releasing hormone (LHRH) agonist/antagonist, whereas in the EMBARK trial “ADT” is restricted to mean treatment with leuprolide (either Lupron or Eligard).
Both trials are already fully enrolled and so it is not possible to enroll in these trials at this time.
In the first case, the changes to the trial protocol will bring the predicted primary completion date for the ARCHES trial forward from April 2020 to late this year (2018), and so we might get the results at the Genitourinary Cancers Symposium in February 2019. In the second case, the changes will bring the predicted primary completion date for the EMBARK trial forward from March 2021 to some time in mid-2020.
We would note that in each case the US Food and Drug Administration (FDA) and probably the European Medicines Agency (EMA) must have agreed to the changes in the trial protocols since the companies are hoping to use the results of the two trials to gain regulatory approval for clinical use of enzalutamide in these two groups of patients.
At present, enzalutamide is only approved for the treatment of men with castration-resistant prostate cancer (CRPC). Of course individuals physicians may choose to prescribe this drug “off-label” if they wish to and if their patients are willing to pay the costs. However, neither Medicare nor any commercial insurer that we are aware of currently covers the costs for treatment of enzalutamide in the treatment of metastatic or non-metastatic HSPC (except, perhaps, under very extraordinary circumstances).
At present we are unable to comment on the potential effectiveness or safety of enzalutamide in these two groups of patients with differing types of HSPC. We — like everyone else — are just going to have to wait to see what the data show us in due course.
Filed under: Diagnosis, Drugs in development, Living with Prostate Cancer, Management, Treatment | Tagged: "high risk", ARCHES, EMBARK, enzalutamide, hormone-sensitive, metastatic, trial |
THE "NEW" PROSTATE CANCER INFOLINK 
I have been on enzalutamide for 3.5 years years. I am hormone sensitive. First it was after an off period from ADT and with a rising PSA that I started Firmagon and enza 4x/day. After a year or so with excellent response the Firmagon was stopped and the enza continued and when T recovered the enza was reduced to 1 pill per day with undetectable PSA. I have since had several changes in dose — to one pill per day 5 days per week (5 pills per week) and then to 2 pills per day where I am now with a low and stable PSA. This is all under the care of Myers and Charles Drake (Columbia NYC).
I had two metastases in 2012 during an off ADT period which were treated successfully with radiotherapy. This prior metastasis may have played a role in drug approval. There has been no problem with BCBS Medicare advantage, and now United Advantage about payments, though it must go through their specified provider and not my local pharmacist. S100 per month until the donut hole is past.
Dear Tarhoosier:
You describe yourself as “hormone-sensitive” and, in the sense that you are clearly responsive to treatment with enzalutamide, that is certainly true. However, “hormone-sensitive” as it has traditionally been used (and as how it is usually applied in clinical trials) means responsive to treatment by orchiectomy, by use of an LHRH agonist (like Lupron) alone, by use of an LHRH agonist + an antiandreogen (like Lupron + Casodex), or by use of an LHRH antagonist (like Firmagon) alone.
In that sense, you would be appropriately described as castration resistant — and that is why your insurance provider has been willing to cover the costs of your enzalutamide to date.
Now please understand that I am not “criticizing” how you describe yourself. The truth is that we have yet to define appropriate language to accurately describe people like you. Arguably, a better way to describe you might be “first-line hormone-resistant; second-line hormone sensitive” — but that’s a bit of a mouthful. We need a new set of terms to be able to accurately define differences like this.
This is more than a philosophical issue. We are very soon going to truly require such language to define who is eligible for clinical trials in men like you who no longer respond to the second-line forms of hormone therapy (and who are therefore really hormone therapy-resistant) and the men who are really only resistant to first-line forms of surgical and medical castration.
It may well be that terms like the following would be more accurate:
— Castration-sensitive prostate cancer (CSPC), to mean a man who is responsive to standard forms of surgical or medical castration
— Castration-resistant prostate cancer (CRPC), to mean a man (like you) who is no longer responsive to standard forms of surgical or medical castration
— Castration-resistant/hormone-sensitive prostate cancer (CR/HSPC), to mean a man (like you) who is no longer responsive to standard forms of surgical or medical castration but who is still sensitive to advanced forms of hormone therapy with drugs like abiraterone acetate, enzalutamide, and apalutamide
— Castration-resistant/hormone-resistant prostate cancer (CR/HRPC), to mean a man who is no longer responsive to standard forms of surgical or medical castration together with to advanced forms of hormone therapy with drugs like abiraterone acetate, enzalutamde, and apalutamide
— Chemotherapy-sensitive prostate cancer (ChSPC), to mean a man who is sensitive to taxane-based chemotherapy
— Chemotherapy-resistant prostate cancer (ChRPC), to mean a man who is no longer responsive to taxane-based chemotherapy
Please understand that I do not see this as the “perfect” terminology: that it isn’t. However, it is potentially illustrative of where we need to go. For example, this terminology takes no account of those men who may be sensitive or resistant to immunological treatments like sipuleucel-T.
Based only on my knowledge of @tarhoosier from what he writes here:
“after an off period from ADT and with a rising PSA (that) I started Firmagon and enza”
… we cannot tell if he was hormone sensitive or hormone resistant without knowing how he responded on resumption of LHRH alone.
If @tarhoosier was resuming IADT, the likelihood is that he was hormone (castrate) sensitive in the “traditional” sense. Snuffy just added enzalutamide for good measure.
I have wondered how Dr. M managed to get these drugs approved by Medicare — and whether he did?
I have never failed to reach an ultrasensitive PSA while using Zoladex, my preferred LHRH drug, usually with Casodex. In 2015 Myers prescribed Firmagon and enzalutamide with the explanation that they were “better” than what he had used before for me. On my next off period I had a rising T and then a rising PSA and the enzalutamide alone was resumed without the concomitant LHRH drug. My current oncologist, Charles Drake, says that he is “99%” sure that a return to LHRH drugs will restore my low PSA, if necessary in the future, in the event of enzalutamide failure.
I believe that men who have a rising PSA on LHRH drugs add enzalutamide or abiraterone, but do not abandon LHRH drugs in order to maintain a low T environment. I have a T of 700+ at this time. I have been on a dose of enzalutamide as low as one pill per day five days per week.
These are the reasons I call myself hormone sensitive.
Dear Tarhoosier (and Rick):
So the off-label use of enzalutamide either alone or in combination with an LHRH agonist or an LHRH antagonist in men who are “traditionally” hormone-sensitive is currently in clinical trials. I would expect clinical trials of apalutamide in this indication too. I would not expect to see Phase III clinical trials of abiraterone acetate in this scenario because of the historic need for this drug to be given in combination with a corticosteroid and the fact that this drug is close to coming off patent. However, you never know …
The question of whether there is long-term benefit to using a drug like enzalutamide or apalutamide as — to all intents and purposes — a first-line monotherapy for progressive prostate cancer (in the same way as we have seen a drug like bicalutamide [Casodex] used in the past is currently unknown. This is exactly what the EMBARK trial was designed to address, while simultaneously addressing the use of combination therapy using traditional forms of castration (medical or surgical) alone or along with enzalutamide.
There is a small set of clinicians who will currently prescribe enzalutamide “off label” in these ways (i.e., as a “better” form of bicalutamide). Cost coverage for the use of enzalutamide in this manner is (maybe) negotiable under the right circumstances, but your sitemaster has no knowledge of how common (or unusual) this may be.
It is also the case that we really won’t know quite how well this strategy works over time until we have data on the follow-up management of enzalutamide monotherapy-resistant prostate cancer. For example, we have no clues that I am aware of as to whether a man who starts treatment on enzalutamide monotherapy, progresses on enzalutamide monotherapy, and then starts on an LHRH agonist (or an LHRH antagonist) will do as well as a man who starts on an LHRH agonist (or on an LHRH antagonist), becomes traditionally castration-resistant, and then adds enzalutamide. Long-term follow-up of men in the EMBARK trial might help to answer this question, it these patients are going to be followed for overall survival outcomes.
And then, of course, there is the issue of the cost of long-term enzalutamide treatment, … which is several times higher than the cost of long-term treatment on an LHRH agonist. As gets pointd out on a regular basis, the cost of long-term LHRH therapy was at one time the single largest drug expense for Medicare every year. Cam Medicare even afford to pay for long-term treatment with enzalutamide?
Sitemaster:
I understand that Tarhoosier is still hormone sensitive, but I like that terminology that makes important distinctions. We already need something like this.