New STAMPEDE data support earlier CHAARTED trial results


So here’s the first important finding that will be presented at the upcoming annual meeting of the American Society for Clinical Oncology (ASCO) annual meeting in Chicago. Data from the UK’s STAMPEDE trial show a significant benefit from combining docetaxel-based chemotherapy with androgen deprivation therapy (ADT) in appropriately selected men.

The abstract of the paper to be presented by James et al. is now available on  the ASCO meeting web site. In addition, there is a relatively detailed article available in The ASCO Post. However, please remember that these data haven’t been formally published as yet.

Here is the quick summary …

James et al. will report data based on the management of 2,962 hormone-naive patients in the UK who were assigned to one of four of the STAMPEDE trial’s nine different treatment arms. The four relevant arms are:

  • Standard of care or SOC, which means at least 3 years of ADT along with local radiation for suitable patients
  • Standard of care + six cycles of docetaxel-based chemotherapy
  • Standard of care + zoledronic acid for 2 years
  • Standard of care + six cycles of docetaxel-based chemotherapy + zoledronic acid for 2 years.

To be eligible for inclusion in the trial, patients had to either have metastatic prostate cancer when joining the trial or have high-risk, locally advanced, node-negative, non-metastatic prostate cancer (stage T3/4N0M0, with a PSA level ≥ 40 ng/ml or a Gleason score of 8 to 10).

The authors report the following results:

  • About 60 percent of study participants had metastatic disease at study entry.
  • Average (median) follow-up was 42 months.
  • 948/2,926 men (32.4 percent) died during the follow-up period.
  • Median overall survival times were
    • 67 months for all men in the standard of care arm
    • 77 months for all men in the standard of care + six cycles of docetaxel arm
    • 43 months for men with metastatic disease at study entry in the standard of care arm
    • 65 months for men with metastatic disease at study entry in the standard of care + six cycles of docetaxel arm
  • The survival benefit from addition of six cycles of docetaxel-based chemotherapy to the standard of care was therefore
    • 10 months for all patients in the study
    • 22 months for the patients with metastatic disease at study entry
  • Addition of docetaxel-based chemotherapy to standard of care also increased time to relapse (biochemical progression) by 38 percent.
  • Docetaxel-based chemotherapy + standard of care was associated with additional toxicity compared with standard of care alone, but such additional side effects were manageable.
  • Few patients discontinued docetaxel due to side effects.
  • There was no survival benefit associated with the addition of zoledronic acid alone to standard of care.
  • There was no additional survival benefit associated with the addition of zoledronic acid to standard of care + 6 cycles of docetaxel-based chemotherapy.

Subject to any unknowns, at this time these results certainly seem to add further, strong support to the suggestion that ADT-naive patients with

  • High-risk, progressive prostate cancer
  • Metastatic prostate cancer, and (especially)
  • Metastatic, high tumor load prostate cancer (as defined in the CHAARTED trial)

are strong candidates for initial treatment with both ADT and at least 6 cycles of docetaxel-based chemotherapy (as opposed to just ADT alone).

From a patient perspective, this is also one more reason why any man with high-risk, progressive or metastatic disease would be wise to at least start transitioning his care from a urologist to an appropriately experienced medical oncologist. The vast majority of urologists are not experienced in the use of agents like docetaxel, and delaying initiation of docetaxel-based chemotherapy may cut significant time from your life. There are certainly exceptions to this rule … but they are the exceptions. In ideal situations, patients will have a urologist who is happy to facilitate a collaborative management process between his or her own practice and a well-qualified medial oncologist. This is most likely to occur within academic medical centers and some types of large, multi-specialty practices.

17 Responses

  1. Great to have this confirmation from the STAMPEDE study of the CHAARTED study results for challenging prostate cancer cases.

    I would have qualified for this study when I was diagnosed and staged back in December 1999 and early 2000. I started Lupron in December 1999, transitioned through addition of Casodex in the late winter to full-blown ADT3 with the addition of Proscar in late summer, and my PSA was dropping sharply from its initial value of 113.6 with a Lupron flare to 125. My recollection is that chemotherapy to support ADT was not on the table at all back then in my discussions with at least a half dozen doctors who were heavily involved with prostate cancer, including some prominent specialists. The CHAARTED trial was not started until more than half a decade later in July 2006, so it was probably not even a gleam in the principal investigator’s eye back in late 1999/early 2000. How greatly have prospects for us improved since those days!

    Had I known what we know now from the CHAARTED and STAMPEDE studies — both benefits and side effects, I would have leaped at an opportunity to add chemo. I have been one of the fortunate men with high-risk disease and did not need chemo to achieve success (with good evidence of a cure due to IMRT [with ADT3] a couple of years ago), but there is no way to know our fate up front. While the CHAARTED results were highly encouraging, it is great to have this confirmation that coupling chemo to ADT yields substantially superior outcomes.

    As encouraging as the CHAARTED and STAMPEDE results are, it is wonderful that men with challenging cases now have some other options as well, thanks to the new drugs that have been approved in the past half-dozen years, including re-purposing of some older drugs (such as statins and perhaps Zetia for lower LDL cholesterol, metformin, and, of course, docetaxel). Another aspect of the impact of the wave of new drugs is that the survival numbers in the CHAARTED and STAMPEDE studies likely would have been further improved for trial participants when their cases had eventually gone downhill on ADT and docetaxel; we can visualize the impact of their putting into play the new drugs, such as Xtandi, Zytiga, Xofigo, Firmagon, etc.) Of course, advances in other technologies, such as imaging and genetic testing, would have also helped some of the participants further extend survival and enhance quality of life. The added survival time offered by these advances has a key additional benefit: during that time, new drugs, other agents, and technologies (such as genetic analysis) will have become available, as will much improved “know how” for using the new tools, involving issues such as priority, combination, sequencing, and timing. For example, using the STAMPEDE median results, a man diagnosed with metastatic disease today and treated with ADT + chemo is projected to be alive for 65 months, which works out to October of 2020. That’s a lot of time to improve the prostate cancer arsenal, and he would probably live substantially beyond that projected date due to the improvements, likely with improvements in quality of life!

  2. I’m glad my care for a challenging case of prostate cancer transitioned early from urologists to oncologists, as recommended by Sitemaster where pharmaceuticals are in play

    I fully endorse Sitemaster’s recommendation to have an appropriately experienced oncologist manage such care rather than a urologist. Oncologists are just far more savvy regarding drugs, their benefits, and managing their side effects, and they tend to keep up with that world, while the urologists are, naturally, concentrating on developments related closely to surgery. In fact, on Tuesday evening an oncologist from a prominent local practice discussed the CHAARTED (US) and STAMPEDE (UK) studies, as well as a related French study that was unproductive for understandable reasons such that there is no detraction from the encouraging results of the US and UK studies. He emphasized that the CHAARTED trial, now buttressed by the STAMPEDE trial, had achieved a practice-changing impact very rapidly.

    (On the other hand, I would not want my oncologist doing surgery for me! LOL)

  3. CHAARTED, STAMPEDE: Implications for Strategies Involving Combinations and Timing

    I suspect that these encouraging results from the CHAARTED and STAMPEDE trials will add to the evidence favoring combinations of agents and early use (where appropriate) in contrast to a sequenced string of single agents, with some of them used late.

    My own therapy since 1999 has involved combinations of agents and early use, rather than using a string of single agents until each plays out, and waiting to use some drugs until late-stage symptoms occur. I credit those strategies combinations and early use for much of my success, though of course I have no way of proving it.

  4. I’ve been on a 31-month vacation from hormone therapy (HT). I was on HT for about 15 months prior to the vacation. When I go back on HT in the future, should my doctors and I now consider adding chemo? Is the data relevant for a IHT guy like me?

    Thanks,

    Jerry

  5. Jerry:

    I don’t think we know the answer to this question yet. If your cancer was more aggressive I might well have said “Yes”, but you seem to be doing extremely well with the IHT, so it is hard to be able to tell you anything useful.

  6. Diagnosed in January 2011 — PSA 880, mets throughout the axial skeleton, Gleason 4 + 5. I was offered but refused the STAMPEDE trial. Currently on Zytiga and have not yet had chemotherapy. So far have lasted 53 months. Still relatively healthy and expect to exceed the 65 months median expectation in the STAMPEDE trial.

  7. ADT use in CHAARTED and STAMPEDE trials apparently was single agent as contrasted to combination therapy

    Based on the information on the CHAARTED trial at ClinicalTrials.gov, a US Government site, ADT in the trial consisted of an LHRH receptor agonist like Lupron or Zoladex, or an LHRH receptor antagonist (Firmagon/degarelix), or orchiectomy, but not a combination with the addition of an antiandrogen, and, ideally to me, a 5-alpha-reductase inhibitor (either Avodart for most patients or finasteride).

    Based on the same site and the reports that have appeared, the form of ADT in the STAMPEDE study also appears to have been single agent, either an ADT drug (not limited/specified) or orchiectomy. However, the “standard of care” for ADT may have been liberally interpreted to include combination therapy or even triple therapy for some men as the clinical trial description does not unequivocally rule out combined ADT therapy.

    While the absence of combined ADT therapy does not diminish or confound the results from these important studies, I would have bet at the outset that the participants would have done even better if they had all had combined or triple ADT instead of single agent ADT.

  8. Hi Jerry,

    I too think you, like me, have done well on IADT. If I had had to face the option of chemo for my own challenging case before starting my second, third, or fourth round of ADT (actually ADT3), having done very well previously, I believe strongly I would not have chosen to add chemo. However, as Sitemaster notes, the alternatives for this scenario have not been put to the test.

  9. Seems like quite a game changer!

    I was on ADT for 3 years with the last year of a PSA < 0.01. Came off Zoladex in March but I have remained on Avodart. Due for another PSA test next week with a meeting with my radiation oncologist the following week.

    Should I be considering the dockets cal regime for when I go back on to Zoladex? Or even sooner?

  10. Philip:

    Re your comment above, what do you mean by “the dockets cal regime”?

  11. Well, the dockets cal is somewhat related to the witches dance. One of my grandsons, in second grade some years back, came home one day and announced to his mother that he had “learned the Witches’ Dance” that day. Intrigued and somewhat alarmed, the mother probed as to just what exactly had happened in class that day. It turned out that the class had learned to recite the U.S. Pledge of Allegiance, which starts “I pledge Allegiance to the flag of the United States of America and to the Republic for which it stands”; my grandson thought that the last three words of that phrase were “Witches’ Dance”.

    I presume the dockets cal is the chemotherapy for which it stands, i.e., docetaxel.

  12. There were some additional details from the presentation that were included in a Medscape article.

    So far, at least, only the subgroup with metastatic disease (M1) enjoyed a survival benefit from early docetaxel. For their “high risk” group (defined as non-metastatic N1 or at least two of either T3/4, PSA ≥ 40 ng/ml, and/or Gleason score ≥ 8), there has been no statistically significant increase in survival so far. The Medscape article says:

    “However, in the other subgroup of patients with advanced but not metastatic disease, the difference in survival was not statistically significant, but these survival data are still immature, Dr James noted. However, docetaxel prolonged the event-free survival by “a substantial amount,” and so it should also be considered in this group, he said.”

    I certainly understand the enthusiasm over any treatment that may prolong survival, but I think it is premature to advocate docetaxel before a diagnosis of metastatic (M1) prostate cancer. And given the CHAARTED study findings, I would like to at least see a breakdown comparing the survival benefit in men with multiple metastases compared to just a few. I hope both of these will be part of the presentation on May 31 and the peer-reviewed publication when it comes out.

  13. Allen:

    While I absolutely agree with your words of caution — up to a point — I gotta tell you that if I was diagnosed tomorrow with the type of high-risk prostate cancer defined in the STAMPEDE study (effectively high-risk prostate cancer that is definitely node-positive and/or potentially micrometastatic), I would be pretty insistent about combining docetaxel with the ADT on a purely personal decision basis.

    Why? Because I would be unlikely to see the sort of published confirmation of the benefit for this type of patient that you are asking for in the next 3 years … but if there is such a benefit I would need to take advantage of the possibility in present time, and the relative downside risks of docetaxel treatment in an otherwise pretty healthy 67-year-old are not negligible but they are certainly not that bad.

    For men with defined co-morbidities or just in a less good state of health overall, I can understand that adding docetaxel to ADT may be a less wise choice until we have better data, but we now have two large trials both showing the same potential (albeit unproven in the non-metastatic patients) as against one much smaller and less well conducted trial (the GETUG trial) that showed no meaningful benefit even in metastatic men.

    What we have here is a classic case of data that is so strongly suggestive of an unconfirmed possibility that each patient (with his doctors) would be well advised to think through the potential risks and benefits for themselves. In the meantime, the ADT-naive men with metastatic disease shouldn’t be too cautious. It’s not as though these data are being “pushed” by any drug company. Both the CHAARTED trial and the STAMPEDE trial were conducted by highly respected groups of researchers who had no commercial axe to grind.

  14. First of all, I want to applaud your efforts to encourage earlier use of docetaxel. Sadly, it is underutilized. Even after CHAARTED, I hear of patients and oncologists who decide to “save it for last,” when it does very little good. I agree too that, while 6 cycles are not a walk in the park, symptoms are manageable and usually not debilitating. In my groups, I point out to men reticent to take it that a small sacrifice in quality-of-life years now may result in a much longer increase in quality of life later.

    There has been debate over whether CHAARTED indicates that docetaxel is good for all men with metastases or just those with multiple metastases. Why not start everyone with mets on docetaxel? Other than the obvious side effect profile, there is the problem of docetaxel resistance which inevitably sets in. Will using it before it’s known to confer a benefit preclude its later use when there are multiple mets and the benefit is clear? No one knows with certainty, and, thank God, we also have Jevtana in our armamentarium, but it is a risk that should be considered.

    As for the “high risk” group, as they defined it, I would much rather see an attempt at a curative approach tried first. The article I submitted to you yesterday shows early evidence (though no RCTs) that ADT + RT may well be curative in the setting of newly diagnosed N1 prostate cancer. I raise the possibility in there that, based on evidence from several Phase 1 and 2 clinical trials, docetaxel may improve those results. For those who are not node positive, there have also been good cure rates, or at least long-term survival, from brachy boost therapy (and perhaps SBRT monotherapy) for high-risk patients. Perhaps their outcomes can be improved by docetaxel as well. Since there is no evidence yet from STAMPEDE that survival is increased in the “high-risk” setting using docetaxel + ADT, I would certainly go for ADT + RT first, with an optional discussion about adjuvant docetaxel.

  15. Very interesting design feature provides flexibility in the STAMPEDE trial

    The “detailed article” linked above makes this notable point about the design of the STAMPEDE trial: “STAMPEDE is the largest randomized clinical trial of treatment for men with prostate cancer ever conducted, with more than 6,500 patients enrolled since 2005. The ongoing study has an innovative multistage, multiarm design that can be modified both to assess new therapies and adapt to changes in the standard of care. The standard of care in the continuously recruiting control arm changes as treatment patterns change. For example, radiation therapy has been added to the mainstay androgen-deprivation therapy for certain patients. As the trial goes on, treatment arms that are found to be ineffective are stopped, and new arms are added to assess the efficacy of emerging treatments, such as novel hormone drugs.”

    I’m enthusiastic about the flexibility in the design that enables it to assess new therapies and adjust to changes in the standard of care. For a long time I’ve felt that typical trial designs are too inflexible; they tend to lock patients in to initial (and also final) protocols that don’t allow flexibility to take advantage of advances in the rapidly evolving field of managing prostate cancer. Flexibility in trial protocols is very important as survival is still heavily weighted in scoring success, and, fortunately, most of us now enjoy long survival, including a substantial majority of us with challenging cases (except those with widespread metastases at diagnosis, where hope for long survival depends on further advances). Therefore, trials must either involve late-stage patients or be very long in order to register meaningful results. Flexibility in the trial protocol allows the patient in a trial to enjoy advances in technology over the long term of a trial. (Per the American Cancer Society web site, survival at the 15-year point in the US is 94%, and that counts all patients, while survival at 5 years for men with distant metastases at diagnosis is just 28%; thanks to fairly widespread screening in the US, only a small portion of patients in the US are in that group.)

  16. Hi Sitemaster.

    It was my preemptive texting at work again!

    I did mean docetaxal regime!

    I would appreciate your feedback on the point I raised previously.

    Many thanks,

    Philip

  17. Dear Philip:

    The data from the STAMPEDE trial and from the earlier CHAARTED trial on the use of docetaxel + ADT apply exclusively to men who were ADT-naive at the time of initiation of therapy. There are no data whatsoever (that I am aware of ) to suggest that using the combination of docetaxel + ADT in a man like you who has previously been treated with ADT would have any significant effect on your long-term outcome.

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