Current management of men with nmCRPC: a review

A new review article in the journal Oncology provides an excellent and relatively brief overview of the current options and recommendations for treatment of men with non-metastatic, castration-resistant prostate cancer (nmCRPC).

Luo et al. walk through the appropriate use of approved drugs like the antiandrogens and the LHRH agonists in the management of nmCRPC as well as the use of drugs that have been approved for treatment of metastatic CRPC but are not yet approved in the treatment of nmCRPC. They also provide summary information about completed and ongoing clinical trials in nmCRPC using drugs like abiraterone acetate (Zytiga) and enzalutamide (Xtandi), as well as trials of drugs that are still investigational and unapproved for any indication as yet (e.g., Prostvac, ARN-509, and ODM-201).

The bottom line recommendation made by the authors is that men who progress to having nmCRPC are best managed by having them participate in clinical trials of potential new treatment options. Other forms of treatment are certainly possible, but neither chemotherapy nor immunotherapy are recommended or approved for the treatment of men with this category of prostate cancer. Readers should be aware that no patients ever get initially diagnosed with nmCRPC; this disease stage is only possible among men who have received androgen deprivation therapy (ADT) prior to any evidence of metastasis but start to progress on ADT despite the continuing absence of evident metastasis.

This article will be a useful resource for prostate cancer support group leaders and other prostate cancer educators. Some additional commentary on the management of nmCRPC is provided by Dawson in association with this article.

5 Responses

  1. Considerations not mentioned in this paper re management for non-metastatic Castration Resistant Prostate Cancer

    Thank you for reviewing this interesting study, which provides some useful data, insights, and thoughts. However, the study appears to omit some important points.

    As a 17th year survivor of a once life-threatening case, managed for 13 years solely on triple ADT, prior to a possible cure with radiation in 2013, the next threat I was concerned about was development of nmCRPC. Therefore, I became familiar with the science and with doctors I considered leading experts. From that successful perspective, several considerations not addressed in the paper deserve mention.

    (1) Use of a testosterone level of < 50 ng/dl as a criterion for CRPC. That is certainly the widely accepted standard and the one routinely used in research studies. However, based on well-documented research, a substantial number of doctors are convinced that a testosterone of 20 or higher suggests inadequate ADT that can be remedied, often resulting in continued successful management of the cancer with ADT instead of a diagnosis of CRPC. Remedial tactics include shortening the dosing interval for patients who clear the ADT drugs unusually rapidly, ensuring proper drug administration, and ensuring proper drug storage. One expert advised that as many as 1 in 10 patients on ADT appear to be treated with inadequate ADT, often leading to unwarranted diagnosis of CRPC.

    (2) No mention of dihydrotestosterone (DHT) monitoring. I found this omission most surprising. Although DHT is metabolized from testosterone, some men make a lot of DHT despite low levels of testosterone. It is well known that DHT is far more potent as a fuel for prostate cancer than testosterone. Therefore, control of DHT is critical for these men. One tactic for minimizing DHT follows next.

    (3) No mention of use of 5-alpha-reductase inhibitor drugs (finasteride/Proscar or dutasteride/Avodart). These drugs have a mild side effect profile for most of us, including some desirable side effects, and they are effective at minimizing the amount of DHT that is converted from testosterone. They also may help by reducing the blood supply to the tumors. One line of thought is that their use makes antiandrogen drugs more effective. The thinking is that (a) antiandrogens work mainly by blocking the cancer cell fuel docking sites (for testosterone, DHT, etc.), but that the earlier generation antiandrogens (flutamide, bicalutamide, nilutamide — not enzalutamide, the most recent generation) still used to treat many of us are not that good at competing with DHT for docking sites (the androgen receptors or ARs); therefore, (b), if you sharply reduce the DHT competing for those sites, the antiandrogens do a much better job of blocking them. (My successful therapy for 13 years, and to support radiation, involved a combination of Lupron, bicalutamide [with flutamide after an apparent possible ARM], and finasteride, later dutasteride, plus supporting drugs.)

    4. Possibly overly pessimistic prognosis for CRPC patients whose cancer has become metastatic. The paper states the following: "… If the disease progresses to metastatic CRPC, the prognosis is poor. The most common site of disease metastasis is bone, followed by lymph nodes, lungs, and liver. … Median survival for this stage is about 3 years with best medical therapy. …" It is important to remember that this estimate is based on survival of patients treated a number of years ago — not in 2016 when advances in drugs, imaging, and management tactics are standard. Also, better ADT, as described above and with superior newer drugs, may be more effective in its role of supporting therapy for CRPC, leading to longer survival. Detection and effective treatment of oligometastatic prostate cancer is also likely to improve overall prognosis, at least to some extent, as some oligometastatic patients will become non-metastatic or even be cured.

  2. Dear Jim:

    I don’t think that Dr. Beer or his coauthors would agree with too many of your comments. Many of these comments are based on the experiences of you and a very small number of other men who may simply have a peculiarly mild form of metastatic prostate cancer. The majority of men who progress to mCRPC from nmCRPC have a distinctly short life expectancy.

  3. I too believe Dr. Beer would disagree. I even think Dr. Oliver Sartor, who is a good friend of at least one of the leading advocates of these practices, Dr. Charles Myers, would disagree with some of what I described above, especially adding a 5-ARI drug, and Dr. Sartor has put a weak form of these practices to the test, with results he considered discouraging.

    Perhaps there is only a handful of doctors who have pioneered and now regularly use these practices, but my impression is that these doctors have a strikingly high percentage of success in their large practices that are dedicated to prostate cancer, with many challenging cases. The lack of acceptance of what they do routinely may be one of the many instances in the history of medicine where great advances are not commonly accepted. I am convinced that is the case.

    A large proportion of the patients in these pioneering practices would have been delighted to learn that they may really have had mild cases. I’ll admit that, for me, a very high baseline PSA, a short doubling time of 3 to 4 months with a projection with no treatment of a PSA in the thousands about a year from diagnosis, all biopsy cores positive, most 100% cancer confirmed by Dr. Jonathan Epstein, and other adverse characteristics sure made me think my case was not mild!

    The prognosis for men who become metastatic has been debated and is still arguable. Some of us, with what we thought were our own challenging cases, who in the early 2000s were thinking that prognosis was as short as indicated in this article, were greatly encouraged by the study authored by Oefelein, Agarwal and Resnickand published in 2004. Disturbed that the short prognosis for metastatic men then current did not match their experience, they did a detailed record review at their institution, Case Western in Cleveland. Their key finding was that “median survival after hormone refractory prostate cancer [today we would call this castration resistant prostate cancer, CRPC, of course] developed in patients initially staged with and without skeletal metastasis was 40 and 68 months, respectively.”

    When I saw that, knowing that I was not yet detectably metastatic, I immediately received an extended lease on life and excitedly told my wife. Yes, the study was neither prospective nor randomized, and yes it was small, involving only 254 men, but it did base the time for the start of CRPC on elevation from PSA nadir rather than from time of enrollment in a clinical trial. To patients, the timing used in the Oefelein study is what matters. Of course there have been numerous and great improvements for such patients since 2004, which suggests a reasonable conclusion that these patients at Case Western would have done even better if they were treated with today’s technology. As someone with education in research as well as related career experience, I know that the “operational definition” of key research terms is critical. In this case, trialists, as a practical necessity, are using an operational definition of time of beginning of CRCP (typically the date of trial enrollment) that is later than the real time of CRCP, likely, in many trials, earlier by a matter of many months if not years. That means that true survival as measured in a treating clinic with regular PSA monitoring, as contrasted to the clinical trial environment, is going to be considerably longer, longer enough to be very good news to patients.

    As a footnote, when the Oefelein findings were described at a prostate cancer research conference session in 2007 that involved a number of prominent trialists in the audience, including Dr. Susan Halabi — well known for her leadership on such prognosis — on the panel, some of the trialists were incredulous. It was impressive that Dr. Halabi was not incredulous; rather, she was very interested in the results and appeared to have an open mind.

  4. Dear Jim:

    Unfortunately the definition of hormone refractory used by Oefelein et al. was not then, and is not now, the standard definition of either “hormone refractory” or “castration resistant”. They defined their patients based on the very first indication of a rise in PSA while on hormone therapy. However, the standard definition requires a rising PSA after at least two different types of hormonal manipulation, inclusive of addition of an antiandrogen (if not already being given) and antiandrogen withdrawal. Such treatment could easily add a year or more to the time from which a patient indicates a first rise in his PSA after being at nadir on an LHRH agonist alone.

    The definition of nmCRPC being used by Luo et al. in their article is based on that definition along with the requirement for three serial rises in the patients’ PSA levels, so you aren’t actually comparing apples to apples at all.

  5. I understand and agree with your point regarding the definition, and you provide important clarification. I was trying to present the patient’s perspective, where we are acutely aware when our PSA starts to rise and continues upward until their is a problem, in this case CRPC. We are intimately aware of that starting point and timetable, which is different from a research starting point and timetable. Where we patients and many of our doctors make a mistake is to apply the published prognosis figures to that first turning upward in PSA, even though that turning is the true starting point — or as close as we will get with actual CRPC beginning between our two last tests — for CRPC. Your “apples to apples” comment kind of makes the point I was striving to make.

    However, it does seem to me that the average patient with suspected CRPC will probably go through the antiandrogen (and hopefully other supportive drugs) routine fairly quickly, with PSA tests at least monthly until the determination is made. If it is true CRPC, the added antiandrogen (which should to many of us have already have been part of the therapy) will prove ineffective within several months, I believe. Several of my own tactical moves were made that quickly (not for CRPC).

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