Sequencing of abiraterone/Zytiga and enzalutamide/Xtandi in men with CRPC

The question of whether it might be better, in certain types of prostate cancer patient, to be treated first with abiraterone acetate (Zytiga) and then with enzalutamide (Xtandi) or the other way around is, as yet, unresolved … and it may depend on the type of patient and his precise clinical status.

A recent study, carried out between the Kyoto University Hospital (including its satellite hospitals) in Kyoto, Japan, and the Johns Hopkins Cancer Center here in Baltimore, MD, has provided us with data from nearly 200 patients that is relevant to this question — but we should say, immediately, that only randomized clinical trials in well-defined sets of patients could actually provide an accurate answer to the question for each definable set of patients. However, with that proviso …

Terada et al. report the results of a retrospective analysis of data from 198 consecutive, chemotherapy-naïve men with castration-resistant prostate cancer (CRPC) who had received abiraterone and enzalutamide for their CRPC. Here is a summary of the relevant findings:

  • Of the 198 patients
    • 113 (57.1 percent) were treated first with abiraterone and then, on progression, with enzalutamide.
    • 85 (42.9 percent) were treated first with enzalutamide and then, on progression, with abiraterone.
  • Average (median), PSA-based, progression-free survival times were as follows:
    • For treatment with the first of the two drugs (i.e., abiraterone or enzalutamide), progression-free survival times were similar (hazard ratio [HR] = 0.88, P = 0.412), i.e., it didn’t matter which of the two drugs was given first.
    • For treatment with the second of the two drugs, progression-free survival was better is enzalutamide was give as the second drug (HR = 0.67, P = 0.009).
    • For the entire course of treatment, the abiraterone-enzalutamide sequence was superior to the enzalutamide-abiraterone sequence on univariate (HR = 0.56, P < 0.001) and on multivariate (HR = 0.65; P = 0.44) analysis.
  • There was no significant difference, however, to overall survival times for either of the two sequences on univariate (HR = 0.88, P = 0.599) or multivariate (HR = 0.81, P = 0.427) analysis.

In other words, it appears from this retrospective cohort study that chemotherapy-naïve patients with CRPC might have a slightly longer progression-free survival on the abiraterone-enzalutamide sequence than on the enzalutamide-abiraterone sequence, but that the sequence has little apparent impact on overall survival.

13 Responses

  1. Just finished 5 years 8 months testosterone control with abiraterone/Zytiga, Lupron, and Avodart. Enzalutamide/Xtandi in the mail from Express Scripts to replace Zytiga and see if controlling androgen receptors will provide me similar longevity.

  2. Neuroendocrine shift risk with Zytiga and Xtandi?

    Chuck: You keep on blazing trails!

    Regarding duration of survival after such therapy, at the PCRI/Us Too conference in September in Los Angeles last year a number of the presenters were aware of a risk of a shift to a neuroendocrine pattern after profound ADT with Zytiga and/or Xtandi, in other words a shift occurring possibly in response to severe removal of testosterone. My sense from the conference is that this was an emerging concern that was not fully understood, and I’m not aware of much news about it. If not countered, such a shift suggests a risk of shorter survival as neuroendocrine disease has such a poor prognosis.

    Dr. Myers stated that estradiol, while it is protecting bone density from ADT, shuts that shift off and can even flip patients who have undergone neuroendorine differentiation back to normal. (Disc 4 2:58:56)

    Any news, thoughts about this matter?

  3. maack1: I hope Xtandi (enzalutamide) works for you. (-:

    A couple of interesting things about this trial for me: (1) I have to assume patients were not metastatic, although I can’t access the full text. (2) Some patients were Japanese, some were from USA. I don’t know the percentage. Mike — did I catch that right?

  4. Jan:

    Like you, I have only seen the abstract of this paper. I would actually assume that this was a mixture of patients with non-metastatic CRPC and metastatic CRPC — but since I haven’t seen the full paper either, I am guessing. I would also guess that the majority were metastatic since the two products are not indicated in the USA for treatment of non-metastatic CRPC.

    Like you, I also have no idea how many of the patients were treated in Kyoto and how many were treated in the Baltimore. If you wanna know you could e-mail the corresponding author (Dr. Osamu Ogawa) and ask for a copy of a PDF of the full paper.

  5. Jim Waldenfels — How are you? What “Disc 4” are you referring to? Thanks

  6. Hi Jan,

    I am doing fine! (PSAs never higher than < 0.05 since that radiation with ADT3 in 2013 — and I remember and remain grateful for your advice on my imaging questions.)

    "Disc 4" is one of the four discs in the DVD pack for the PCRI/Us TOO 2016 Conference on Prostate Cancer, which is of course available from PCRI as I'm sure you know. Disc 4 covers Meet the Speaker Q&A (questions from patients, not from Drs. Scholz or Moyad) for Drs Howard Sandler, Eugene Kwon, Nicholas Vogelzang, and Charles "Snuffy" Myers. Each session is roughly 45 minutes in length.

    Our Us Too chapter always buys the DVD set from the conference, and I have found the sets extremely useful. It's nice to be able to pause on some of the complex slides, perhaps doing a PrintScreen, and to make accurate notes at a reasonable pace, which is not really possible during the conference itself. (Still, I have always greatly enjoyed those conferences and hope to return. My wife's stroke in 2013 has made it difficult for us to travel.)

  7. I have completed a trial with Xtandi in British Columbia, Canada, but now am withdrawn from this trial.

    I do not know about Zytiga. Is Zytiga available (with a steroid) within my province following the standard protocols.

  8. Message for Jim Waldenfelds:

    My first time on this site.

    I am a person with the neuroendocrine shift that Dr. Myers indicated. I am in British Columbia, Canada I hope you can help. I was enzalutimide but now stopped.

    Jim you mentioned disc 4. Can that be accessed?

  9. Dear lplarry:

    Zytiga is certainly available in BC, but only for men who have metastatic, castration-resistant prostate cancer I believe. You would need to ask your doctor(s) whether it was appropriate and available for you because it would depend on your precise clinical circumstances.

    I note that in the message you left for Jim Waldenfels you stated that you had had a “neuroendocrine shift”. What I can tell you is that if you now have a neuroendrocrine form of metastatic prostate cancer after treatment with Xtandi, abiraterone acetate (Zytiga) may not be the most appropriate form of therapy to use next. This makes it even more important that you discuss this with your doctor.

  10. Thanks,

    I am a learning phase of deciphering what are the rules or protocols that are standard treatments are what are permissible deviations from these procedures.

    I am going for a second medical opinion from a medical oncology doctor who helps patients explore cutting edge deviations such as provided by Dr. Stuffy Myers. I have a hunch my Xtandi treatment, when shutting down my testosterone, may have triggered what you refer to as a neuroendocrine shift so I now have two cancers. I was scheduled for prostate immunotherapy but with this shift immunotherapy was taken off the table of procedures available.

    My intent now is to learn the available cutting-edge procedures such as your reference to an emerging procedure that may shift the neuroendocrine mutation back to (normal). In other words, resetting my neuroendocrine cancer.

    I also wonder why I could not receive the immunotherapy procedure planned.

    I do not expect (a) particular answer, only the opportunity to learn in order to ask the most relevant questions when I go for a second opinion from an accredited doctor. This second doctor, who is comfortable deviating from established protocols that are rule-based medical treatments does offer these deviations that can be applied in my personal case; for example sequencing a larger portion of my cancer gene path, offering immunotherapy as a second step after chemotherapy.

    Dr. Myers is a promising lead to follow which this thread has introduced me to. With my focused story I hope to generate other relevant leads and to become acquainted with emerging science based options.

    Thanks for replying and to all the others who I hope may chime in.


  11. Dear Larry(?):

    At the present time there are no “approved” therapies that are known to be consistently effective in the treatment of neuroendocrine cancers, and there is only a small number of medical oncologists who have real experience in treating this type of prostate cancer. Certain types of chemotherapy do work in some patients, and a lot depends on exactly which type of neuroendocrine cancer has been “triggered” in your specific case.

    I would strongly encourage you to ask the medical oncologist about clinical trials of new types of therapy that are being developed specifically to treat these types of neuroendocrine cancer. We know that some types of chemotherapy can work for some patients and that a drug called pembrolizumab (Keytruda) may work in relatively rare patients with certain very specific types of cancer (see here).

    I can’t tell you exactly why whatever form of immunotherapy you were scheduled for was cancelled, but if that immunotherapy was going to be sipuleucel-T (Provenge), we know this form of treatment is not effective in men with neuroendocrine forms of prostate cancer.

    Finally, re Dr. Myers … He is no longer a young man, and I have been told that he is no longer accepting new patients.

  12. Thank you for your help. At this point I am following these leads in order to prepare to ask the right questions when I go to see my oncologist. As you say, the exploration of neuroendocrine shifts is rare and few oncologists specialize in this arena.

    Thanks for this guidance


  13. Hi Larry,

    The DVD sets are available from the primary conference producer, the Prostate Cancer Research Institute. My understanding is that the requested donation is $150 for an individual, but $75 for an educational/support group. You may be able to find a support group that has a set to loan to you. The next conference is fast approaching (September 8-10 in LA at the Los Angeles Airport Marriott), and DVD sets from previous years are usually available at a sharp discount. I expect the 2016 set will be offered for $30 at that time.

    You are really fortunate that you have awesome prostate cancer resources available in British Columbia. While Canada has some sites with high level expertise in various locations, I think of Toronto and Vancouver as the leaders, in fact at the forefront of world-wide research in some areas. That has certainly been the case with my own therapy for 14 years (before a curative attempt, apparently successful, with radiation in 2013 after improvements in technology). Some of the names familiar to me are Drs. Bruchovsky, Goldenberg, and Gleave. I just used their names to do a search of the US government’s wonderful PubMed website, and got 70 hits related to neuroendocrine and small cell prostate cancer with the following search string: (gleave m [au] OR bruchovsky n [au] OR goldenberg [au]) AND prostate cancer AND (small cell OR neuroendocrine). You can do the same, and by clicking the author information button (“+”) for any abstract you have called up, you can see if it was primarily the work of Vancouver or another institution in British Columbia, as well as which of the authors were associated with BC institutions. It appears you already may have been able to access some leading-edge expertise.

    Dr. Myers has announced he is retiring, but I have not kept track of the date. He has certainly earned it, but I’m hoping he will continue his research and insight-sharing in the coming years. He is scheduled to present at this year’s conference in LA.

    Good luck to you.

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