Update on late stage, “intermediate atypical” mCRPC

According to a report this morning on the UroToday web site, Dr. Eric Small presented an update yesterday on so-called “intermediate atypical”, metastatic, castration-resistant prostate cancer (mCRPC) — at a general session of the 2015 meeting of the Society of Urologic Oncology in Washington, DC. Small and his colleagues had reported previously on this issue at the ASCO meeting this year (see here).

In this latest update, on behalf of colleagues in a six-center “Dream Team”, Small updated attendees on the research team’s attempts to identify and to target “adaptive pathways” among men with metastatic CRPC who had also exhibited resistance to treatment with abiraterone acetate (Zytiga), enzalutamide (Xtandi), or both of these newer drugs. To do this, the research team has been biopsying metastatic tumors in such patients while also conducting regular clinical assessments and testing serum, plasma, and blood draws for circulating tumor cells (CTCs). The vast majority of the biopsies have been from metastatic bone tissue; other biopsies have been carried out from lymph nodes and from metastases to the liver, the lungs, the adrenal glands, the brain, the bladder, and other “soft tissues”

Small reported that, as of the time of his presentation:

  • A total of 220 biopsies had been carried out.
  • The protocol had an overall success rate of 78 percent, with the lowest success rate in bone (65 percent).
  • 38 percent of 158 evaluable biopsies were pure adenocarcinoma.
  • 11 percent were small cell neuroendocrine tumors (possibly because these patients are heavily pre-treated).
  • 29 percent were a new entity labeled “intermediate atypical carcinoma” (IAC), which is histologically distinct from both small cell carcinoma and adenocarcinoma.
  • IAC appears to have histologically unique and reproducible microscopic features.
  • Patients with IAC also appear to have a shorter average survival time that patients with pure denocarcinoma.
    • 25.8 months for adenocarcinoma
    • 19.1 months for IAC
  • As for metastases, there is no clear pattern to presence of IAC in specific sites of metastatic disease; IAC can be found in all metastatic tissues.

Small emphasized that clinicians should to avoid any presumption that the liver harbors aggressive variants or that lymph node generally harbors less aggressive variants (more commonly have non-adeno).  In fact, one in three metastatic sites in the liver is pure adenocarcinoma and lymph node metastases in this study seemed to more commonly have non-adenomatous mertastasis (i.e., small cell carcinoma or IAC). He also reported that a 50-gene signature and a full gene set signature have already been identified and additional genetic studies are being conducted.

5 Responses

  1. Is there any reporting of whether the patients who have these variants of prostate cancer had them from the time of diagnosis, or whether there has been a transformation or mutation of the cells over time? If the latter, is there any consensus of whether the transformation or mutation is merely the result of the natural history of prostate cancer, or instead related to the type of treatment (e.g., long-term ADT) the patient has had over the years? Thank you.


  2. Dear Richard:

    I don’t believe that we have a straightforward answer to this question as yet. It is clear that in at least some patients there is mutation over time, but whether this is always directly associated with the specific treatments received has (as I understand the situation) still to be clarified.

    Conversely, there is quite certainly a very small subset of patients who start out with neurondocrine cancers (certainly including small call cancers of the prostate).

    The IAC type of cancer has, however, (as far as I am aware) never been identified in any patient who has not received various types of long-term treatment, usually including ADT, chemotherapy, and use of either enzalutamide or abiraterone acetate.

    What has been happening is that we have been seeing an increase in these types of neuroendocrine cancers in patients with last stage disease as we have been able to keep them alive longer with chemotherapy and with the newer types of drug therapy. What is more difficult to know is whether the changes in histology is a direct consequence of the newer types of therapy or is simply a consequence of the cancers having longer to undergo serial mutations.

  3. I heard a very similar presentation from Dr. Small back in September, although he reported on a few less biopsies. The target is 300 so men who are resistant to both abiraterone and enzalutamide can still reach out for inclusion in the Dream Team West sample — they are recruiting. One benefit is that it provides whole genomic sequencing that might possibly identify actionable genes. It should be done sooner rather than later — especially if blood counts are already compromised.

    In conversation I got the strong impression that in most of these cases, their prostate cancer has mutated. Last week I accompanied a patient to a consult with one of the senior UCSF genitourinary med/oncs who specifically said this. He spoke of changing into a state of “dedifferentiation” where the prostate cancer cells may also produce less PSA. In this specific case, the man’s PSA has fallen from 4,300 to 67 since starting enzalutamide in August; at the same time the disease has spread viscerally from bone to liver — sadly, he invoked hospice this week.

    Again, based on discussion alone, the hypothesis is that the disease morphs in response to drugs administered. This is one reason why many of the NCCN genitourinary med/oncs do not employ protocols that combine hormone therapies, especially early in the disease.

    All anecdotal so far — please don’t shoot the messenger. ;-) !!

  4. Rick,

    I’ll put my gun back in its holster ;-) But I did want to raise the alternative response to the fact that hormonals exert selective pressure on the cancer towards resistance. The alternative hypothesis is that combining hormonals early may block the cancer from adopting the survival mechanisms it uses when those drugs are administered one at a time. This is the therapeutic strategy that has been used so effectively in devising chemo cocktails for other cancers. There are many such combo trials in the works (e.g., Xtandi + Zytiga + Lupron, and also hormonals + growth factor inhibitors), but until we have those results, we can’t say whether it delays, speeds up, or has no effect on progression, or whether there are subsets of patients that will or will not respond.

  5. Rick,

    A long time ago I put my bet on the alternative hypothesis that Allen mentioned: combined therapy — in fact, for me, triple therapy plus supporting drugs and lifestyle tactics.

    It is well known that for many of us on an LHRH agonist drug the body senses the shortage of testosterone and signals the adrenals to make more. For some of us the adrenal response is fairly limited — a nominal amount of added testosterone. For others, if memory is serving me well and I think it is, up to 40% of normal testosterone can remain due to direct and indirect adrenal impact. (That percentage may not be a sound number as it is possible that other causes, such as inadequate LHRH agonist delivery, were not ruled out.) Research has established that androgen receptors tends to undergo change too, such as becoming more prominent per each cancer cell.

    I won’t go into the details of triple therapy unless you ask, but it worked well for my challenging case and for some other men I have known with challenging cases. (My baseline, first ever PSA was 113.6, collected just over 16 years ago on December 4, 1999; other details: stage III with a “rock hard prostate throughout” and suspected seminal vesicle invasion; all biopsy cores positive; most 100% cancer; perineural invasion; Gleason (Epstein) 4 + 3 = 7; doubling time 3 to 4 months.) I was on intermittent ADT3 for a little more than 13 years, with the last of four rounds of ADT3 supporting an attempt at cure with radiation that looks good so far (PSA not exceeding < 0.05, the lower limit of the current test being used). Each time I achieved a nadir of 0.02 or lower.

    The doctors I have followed closely since 2000 are convinced the opposite of what you wrote is true: they believe that using single drugs in sequence allows the cancer to adapt to defeat each drug in sequence, while combining the drugs gives the cancer nowhere to go. However, my strong impression is that many doctors do not employ combinations, especially early in the disease, just as you wrote. I'm convinced that this is a profoundly flawed approach but cannot provide conclusive evidence. There is a fair amount of suggestive formally published evidence favoring combined therapy.

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