Time to death among men with nmCRPC by NCCN risk group

One of the abstracts to be presented at ASCO this year gives us some insight into risk for and time to death among men with non-metastatic but castration-resistant prostate cancer (nmCRPC). This is a group of men for whom therapeutic options are currently poorly defined and of limited effectiveness.

Macomson et al. used data from the Optum electronic health database to identify a total of 1,008 men who met all relevant criteria for a diagnosis of nmCRPC between 2007 and 2016.

They categorized these men into one of four different risk groups:

  • Group A: Men initially diagnosed with NCCN low-risk prostate cancer (Gleason ≤ 6 and PSA < 10 ng/ml)
  • Group B: Men initially diagnosed with a PSA level of < 10 ng/ml and who had no assigned Gleason score
  • Group C: Men initially diagnosed with NCCN intermediate-risk prostate cancer (Gleason = 7 or PSA ≥ 10 and ≤ 20 ng/ml)
  • Group D: Men initially diagnosed with NCCN high-risk prostate cancer (Gleason ≥ 8 or PSA > 20 ng/ml).

Here is a summary of the study findings:

  • The average (mean) age of the patients was 76 years.
  • 121/1,008 patients (12 percent) were African Americans.
  • 553/1,008 patients (percent) developed metastases.
  • 430/1,008 (percent) patients died during follow-up.
  • Average (mean) time to metastasis was
    • 28 months for men in Group A (among 9/29 patients or 31 percent)
    • 22 months for men in Group B (among 131/285 patients or 46 percent)
    • 15 months for men in Group C (among 175/320 patients or 55 percent)
    • 13 months for men in Group D (among 238/374 patients or 64 percent)
  • Average (mean) time to death was
    • 32 months for men in Group A (among 8/29 patients or 28 percent)
    • 30 months for men in Group B (among 101/285 patients or 35 percent)
    • 24 months for men in Group C (among 124/320 patients or 39 percent),
    • 21 months for men in Group D (among 197/374 patients or 53 percent)
  • Men in Group D (the high-risk group) were more likely to develop metastasis during the first year and die within the first 2 years than those in any other risk group.

What is probably still surprising about these “real world” data is that

  • More than half of nmCRPC patients with high-risk disease still die within 21 months of onset of nmCRPC.
  • Nearly 40 percent of nmCRPC patients with intermediate-risk disease still die within 2 years of onset of nmCRPC.

We are very clearly still dealing with a subset of men with an aggressive form (or forms) of prostate cancer who are at very high risk for early metastasis and death once they stop responding to standard forms of androgen deprivation therapy (ADT).

9 Responses

  1. Either I don’t understand this summary or there are problems in phraseology.

    First: The eight sub-bullets purport to report the “average (mean) time to” an event. I think this is wrong, and I suspect that what is reported is average (median) instead. Why?

    — The mean cannot be calculated until the entire population has encountered metastasis and/or death.

    — The two final bullets conclude something about “half the men”, surely indicating median rather than mean.

    This is not as nitpick-y as some of my past statistical comments have been. In a population of this sort, the two “averages” can be quite different, and their interpretation is quite different.

    Secondly: I don’t understand what was meant by this phraseology: “months for men in Group (among M1/M2 patients …)”

    Whether median or mean, how was itcalculated?

    — If median, it must have been a projection, not a calculation, for those groups where fewer than 50% had encountered the event.

    — If mean, how was the tail of the curve projected?

    Thirdly: It seems odd to stratify men according to their initial diagnostic findings, when (IIRC) 20% of men who undergo second — or subsequent — biopsies and 30% of men who undergo surgery have upgraded Gleason scores. (Mine is such a case.)

    Fourthly: It is worthwhile noting that the time to metastasis and time to death are measured from the diagnosis specifically with castration-resistant prostate cancer (CRPC) — a diagnosis that might occur decades after the initial diagnosis.

    Finally: It would have been helpful to compare this cohort of men with two cohorts of similar demographics (age, race, co-morbidities) each with one key difference: (a) men without prostate cancer, and (b) men with hormone-responsive nonmetastatic prostate cancer.

    Off the top of my head, I couldn’t tell you whether a man in Group A could expect to live another 100 months or 400 as a median or mean, or whether a man in Group B could expect to live another 50 months or 500 as a median or mean.

  2. So, this begs the question, “Why are there almost no clinical trials open to nmCRPC patients?” Why do these men have to wait until they are metastatic before they become eligible for clinical trials?

  3. Dear Paul:

    I agree with you that this abstract was very poorly written. I haven’t seen the text of the full paper. I did the best I could, but some of your comments and criticisms may be entirely accurate, and frankly I couldn’t tell when the authors were applying the NCCN criteria to these patients, but the “customary” time to do this is at initial diagnosis, not later on.

  4. Dear Len:

    Actually if you really looked through ClinicalTrials.gov (which is hard work) you might find many more trials of men with nmCRPC than you expected. However, …

    (1) One of the biggest problems is that until only a few years ago we had no good drugs that might have been expected to be effective and safe in the treatment of nmCRPC.

    (2) A second problem is that abiraterone acetate (Zytiga) will lose patent protection before any trial of this drug in treatment of nmCRPC could report results, so the manufacturer would have had to make a huge investment in such a trial with no likelihhod of a significant financial return on that investment.

    (3) The manufacturer of enzalutamide (Xtandi) chose to “skip” the nmCRPC patient group and go directly to whether adding enzalutamide to radiation therapy and surgery in high-risk patients could show a clinical benefit. I assume this was a straightforward business decision.

    (4) As a consequence, most trials of drugs in nmCRPC are small Phase II trials at one or two institutions that have not led to any major findings of clinical benefit that would encourage the necessary major investment in Phase III trials that are needed to lead to the approval of drugs for that indication by the FDA.

  5. I think it’s worth mentioning a few points:

    • As always, when they say “metastatic” or “non-metastatic,” they really mean “not detectably metastatic or non-metastatic based on whatever diagnostic methods were used (typically bone scan/CT).

    • Non-metastatic and castration-resistant is a relatively rare situation. Usually castration resistance sets in well after metastases have been discovered. Sometimes these rare types are quite virulent, but not always.

    • To PaulC’s point about means and medians — this was a retrospective data analysis and not a prospective trial. That means they did know what the mean was because they have hindsight. I think (but don’t hold me to it) what they did is remove the zeros — so more accurately, they should have stated: “among those who died/developed metastases, the mean time to death/developing metastases was X.” But I agree that looking at the survival/metastasis curves would be more enlightening.

    • To Len’s point — Because of the rarity of this presentation, such clinical trials are very hard to recruit for. We have discussed on this site one such trial I am extremely hopeful about, and which I understand is going through a very slow recruitment process. That would be the be the trial of Lu-177-J591 + ketoconazole (see this link).

  6. Allen, I agree that there is a false distinction between nmCRPC and mCRPC and I’m sure most medical oncologists would agree, so why can’t practitioners and insurers agree to open up all therapies, whether approved or in clinical trials, for patients as soon as they become CRPC? This would allow such patients to have an earlier start with therapies like enzalutamide, abiraterone, Provenge, etc., instead of standing around while the cancer advances to the point of radiographic progression. Do we really need to prove (through clinical trials?) that nmCRPC will eventually progress to mCRPC?

    Regarding the lutetium-177 trial, I suspect that recruitment is very slow because this trial was first designed (I think) before abiraterone was approved, so they used ketoconazole which has since been completely displaced by abiraterone. If they modified the protocol to substitute abiraterone for ketoconazole, I’ll bet recruitment could be accelerated. I think that Mike’s comment earlier about Zytiga losing patent protection before any current trials could yield results may not apply here because the manufacturer could apply for a “use patent” (to extend the life of the original patent) for the combination of Zytiga with Lu-177.

  7. Dear Len:

    No insurance company (or Medicare) is going to “open up” use of approved therapies for patients as soon as they become nmCRPC for the very simple reason that they aren’t approved for such treatment by regulatory authorities because we don’t yet know whether patients who are non-metastatic will benefit from any such available therapy. The cost risk for the insurance companies is too high. Also, any patient who is nmCRPC can already enroll in any clinical trial they are eligible for (usually at no cost).

    And respectfully, I am pretty sure the costs involved in conducting a trial of abiraterone + Lu-177 in men with nmCRPC would be far higher than any amount of money the company could hope to recover within the possible 3-year patent extension that was exclusive to the use of Lu-177 + abiraterone in men with nmCRPC, which is a small subset of patients.

    With regard to the issue of slow enrollment in the Lu-177 + ketoconazole trial, I think it is much more likely that at the time this trial was being designed the manufacturer of abiraterone acetate was unwilling to have this (at the time) pretty much untested drug (Lu-177) be given in combination with abiraterone because of the risk for unknown side effects. Therefore they wouldn’t have been willing to contribute free drug for conduct of the trial. The consequence of that was that — since abiraterone is not approved for the treatment of nmCRPC — patients would have had to pay for the abiraterone themselves (or the developers of Lu-177 would have). That would have been a pretty hefty bill for anyone to be paying.

  8. The reason that clinical trials are such powerful evidence is because the protocols are uniform. If, for example, a man with nmCRPC has a very different reaction to some treatment compared to a man with mCRPC, then the overall results are “polluted” by the inclusion of two very disparate groups. Imagine a clinical trial for a new hormonal agent, for example, that allowed in a man with small cell prostate cancer that wasn’t detectably metastatic and was CRPC. He will not respond to any hormonal agent, and his inclusion in the total will make the results seem worse than they really are.

    The lead investigator told me that recruiting is slow because it is a rare group — not because it doesn’t include Zytiga. Zytiga is only approved for mCRPC, so including it in a clinical trial for Lu-177-PSMA would doubly confuse the results — what caused the benefit, if there was one? Since such patients could not get Zytiga, they would probably be thrilled to have the option of the nuclear medicine with ketoconazole. They could always get Zytiga later, after they developed detactable metastases (if they ever did).

  9. Still Puzzled After All These Years: Discrepant Survival Medians For CRPC Survival: Oefelein 60 Months (Median) Vs. Halabi 2014 Updated Nomogram For Metastatic Patients (17 – 30 Months, Median), And This Abstract For CRPC Patients (21-32 Months, Reportedly The Mean)

    The survival durations reported above strike me as within striking distance of the typical ranges for prognosis of overall survival for men with metastatic CRPC to be treated with first line chemotherapy, per the well-known and now updated (2014) Halabi nomogram, which is fairly close in survival duration to the prior 2003 version. Granted, it generally takes a little time for men to move from CRPC, as in the above abstract, to metastatic disease, as in the Halabi nomogram, but the above abstract suggests that the time is fairly short in the above study for the minority of men dying early, about 4 to 8 months for groups A to D.

    However, in a 2004 paper in the Journal of Urology, three authors from Case Western Reserve University (Cleveland), Oefelein MG1, Agarwal PK, and Resnick MI, presented quite different prognoses for patients with what was then called “hormone refractory” prostate cancer (now known as CRPC). Case Western Reserve is noted as a prostate cancer research institution, and the late Dr. Resnick was a distinguished leader in the field, once head of the American Urological Association. Here is a link to their paper. In essence, they were struck by their impression, which they were able to prove, of substantially longer survival durations of hormone refractory (CRPC) patients at their institution than the norms commonly reported. Here is the key line from their results: “Median survival after hormone refractory prostate cancer developed in patients initially staged with and without skeletal metastasis was 40 and 68 months, respectively.”

    By the way, as one of about 100 survivor representatives present, I was able to highlight the encouraging Oefelein survival figures with an audience question to the panel on which Dr. Susan Halabi, Dr. Nick Vogelzang, Dr. Eric Small, Dr. Howard Scher, and Dr. Ou were participating at the 2007 IMPaCT Conference (Innovative Minds in Prostate Cancer Today), which was a review of results of sponsored research and an exchange of expert views under the auspices of the US Department of Defense managed Prostate Cancer Research Program of the Congressionally Directed Medical Research Program (CDMRP). The panel was Symposium Sub-Session 18-5 entitled “A Novel Intermediate Endpoint for Predicting Overall Survival in Men with Metastatic Castration-recurrent Prostate Cancer (CRPC): An Analysis of Nine CALGB Studies.” At that time the 2003 Halabi Nomogram was current. My question created quite a stir, with Dr. Vogelzang asserting with some spirit that the figures I had mentioned must be flawed. I was really impressed that Dr. Halabi approached me afterward to get the exact citation of the Oefelein study. This memory is why I put “after all these years” in the title. (And it’s an example of some of the cool and meaningful contributions we survivors can make as activists, challenging the conventional wisdom!)

    But back to the main point: what accounts for the marked difference in survival figures? Perhaps a key factor for the above study is that most men were still alive as of the study’s cut off (72%, 65%, 61% and 47% for groups A, B, C, and D respectively), whereas the Oefelein study was mature as all patients were no longer alive. These facts suggest that final survival time figures will be considerably larger than in this interim analysis of the above study when all patients in groups A through D have passed on. Indeed, nearly half the men in the study had not yet even developed metastatic disease, with figures for those who had metastatic disease ranging from about a third, about half, about half, to about two thirds for groups A through D respectively.

    One minor difference, perhaps adding one to a few months added survival for those dying early, which may not represent the situation for the total group, is the difference in starting the survival clock; the Oefelein study counted time from the first PSA increase (in a series of increases) for men being treated with ADT who had a “castrate level of testosterone,” very likely < 50 ng/dl which was in contrast to starting the clock at the second increased PSA result in the above abstract. That said, men in the above abstracted study were likely monitored with frequent PSA tests, perhaps as frequently as each month, so the average gap between the first and second PSA increase may have been short.

    The Halabi nomogram is based on research where the clock was started at the time of trial enrollment, which might lag considerably behind the first detection of metastatic disease, which in turn usually lags development of metastatic disease. This would seem to explain some of the difference between median survival of 48 months for men with metastatic disease in the Oefelein study and the considerably shorter survival ranges indicated by even the updated 2014 Halabi nomogram. Also, as noted above, the Halabi nomogram does not include time from the first indication of CRPC to the first indication of metastatic disease. (Additionally, it specifically is geared for use of docetaxel and does not cover use of the exciting drugs approved in recent years.)

    What does all this mean for us? I am convinced it means that survival is almost surely substantially longer for us after diagnosis of CRPC than is evident from the above study. The study, at its current state of maturity (with a majority still alive at the research cut-off date), is arguably somewhat helpful in suggesting a rough lower boundary for the length of survival for men with CRPC who may be expected to have shorter than average survival after developing CRPC. For me personally, when I became aware of the Oefelein study — probably around the fifth year into a still life-threatening case under treatment with intermittent triple ADT at that time — I was overjoyed! I knew I was not yet in the CRPC state, and that meant I would likely enjoy at least a number of years before becoming resistant to ADT (never happened by the 14th year, when I ceased ADT, except dutasteride as part of my safety net) and then would likely enjoy around 5 more years of survival, with advances in technology each year that might help me beat this thing. (My PSA of May 10 — 4 years and a month after a curative attempt with radiation, and 3 years and a month after my supportive triple ADT expired — was again < 0.05.)

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