Long-term follow-up data from the CHAARTED trial


At the time of the original presentation of data from the CHAARTED trial, the median follow-up for patients enrolled in this trial was 28.9 months. We now have data from the same 790 patients followed for a median of 53.7 months.

The new paper by Kyriakopoulos et al. has just been published in the Journal of Clinical Oncology. Only the abstract is available on line, and we expect that more detail may be available at the upcoming Genitourinary Oncology Symposium in San Francisco.

Just as a quick reminder, the CHAARTED trial divided patients newly diagnosed with metastatic prostate cancer into two subsets: those with “high-volume”, hormone-sensitive, metastatic prostate cancer and those with “low-volume”, hormone-sensitive, metastatic disease. To have “high-volume” disease a patient had to have

  • Either four or more metastases to bone, with at least one outside of the vertebral column and pelvis
  • Or at least one visceral (soft tissue) metastasis

If patients did not meet the criteria for high-volume metastasis then, by default, they were classified as having low-volume metastatic disease.

All patients were then randomized to treatment with

  • Either androgen deprivation therapy (ADT) + docetaxel (75 mg/m2 for up to six cycles)
  • Or ADT alone

In the initial paper published by Sweeney et al. in the New England Journal of Medicine in 2015, the authors reported that, at a median follow-up of 28.9 months:

  • The median overall survival (OS) for all patients (n = 790) was
    • 57.6 months for those receiving combination chemohormonal therapy
    • 44.0 months for those receiving ADT alone
    • With a hazard ratio (HR) of 0.61
  • The median OS for patients with high-volume disease (n = 513) was
    • 49.2 months for those receiving combination chemohormonal therapy
    • 32.2 months for those receiving ADT alone
    • With an HR of 0.60
  • For patients with low-volume disease (n = 277)
    • Median survival had not been reached

In the new paper by Kyriakopoulos et al., at a median follow-up of 53.7 months, the authors now report that:

  • The median overall survival (OS) for all patients (n = 790) was
    • 57.6 months for those receiving combination chemohormonal therapy
    • 47.2 months for those receiving ADT alone
    • With a hazard ratio (HR) of 0.72
  • The median OS for patients with high-volume disease (n = 513) was
    • 51.2 months for those receiving combination chemohormonal therapy
    • 34.4 months for those receiving ADT alone
    • With an HR of 0.63
  • For patients with low-volume disease (n = 277)
    • No OS benefit was observed
    • The HR was 1.04

Basically, the authors conclude that, at about 5.5 years of follow-up:

The clinical benefit from chemohormonal therapy in prolonging OS was confirmed for patients with high-volume disease; however, for patients with low-volume disease, no OS benefit was discerned.

There are two basic ways to look at these data. One alternative is to take the “glass half full” approach, which is to say that we now know that combination chemohormonal therapy is of great benefit in extending the long-term survival of men diagnosed with high-risk, high-volume prostate cancer (if they have not been treated earlier according to protocols defined in the STAMPEDE and in the LATITUDE trials). The other is to take the “glass half empty” approach one and ask “Why would the low-volume patients not gain a similar benefit?”

Perhaps a more constructive way to look at this is to remember that we do indeed have the data from the STAMPEDE and the LATITUDE trials, which suggest that for men with lower volumes of metastatic disease (and even just micrometastatic disease) the combinations of radiation + ADT + chemotherapy and ADT + abiraterone + prednisone have both been shown to improve long-term survival compared to ADT alone. Thus, we now have three highly effective forms of therapy for first-line treatment of men with low-volume or high-volume, hormone-sensitive, metastatic prostate cancer. The issue is only when to apply which one for the greatest potential benefit in an individual patient.

10 Responses

  1. Sitemaster,

    Can any data from the CHAARTED trial be mined to determine if quality of life was better or worse during the extended survival period when a patient is treated with ADT + docetaxel compared to ADT alone? I just read an article by Dr. Sartor where he examined the data from the LATITUDE trial to conclude that quality of life was actually better in the ADT + abiraterone arm than the ADT + placebo arm (see here).

    Thank you.

    Richard

  2. Dear Richard:

    I would assume that yes, that could be done — again. One study has already been reported on this precise subject, based on the early data from CHAARTED.

  3. Do we have any data on ADT + Xtandi vs ADT + chemo for low volume disease?

  4. Jerry:

    Not that I am aware of (yet).

  5. Blowing the old “18 month to 24 month survival” for metastatic prostate cancer out of the water

    We still occasional hear that ADT will work for only a limited time for men with metastatic prostate cancer, and then death will not be far behind. I recall often seeing and hearing, especially in the early 2000s, figures like 18 to 24 months for survival after development of metastatic prostate cancer. For some time there has been evidence that this is an over-generalization, and the CHAARTED results provide additional evidence.

    While I could not get details from the new paper, the earlier paper shows that even for “high volume disease” overall survival at the 3-year point was slightly above 40% for ADT alone, and slightly above 60% for the combination with chemotherapy. For “low volume disease” at the 5-year point — 2 years further along, overall survival was around 60% for ADT alone, and around 70% for the combo. Obviously, these results are much better than the old, conventionally accepted figures.

    Moreover, I believe that follow-up time for the CHAARTED trial started with either the date of trial enrollment or the date of randomization, as this is the typical practice. Therefore, the above time spans are the minimum spans for survival aided by ADT after diagnosis of metastatic disease. However, the study documents that prior time on ADT was quite short, and it is likely that patients would have been started on ADT rapidly after detection of metastases, so not much time would be added by counting the gap to the starting gun for CHAARTED.

    Regarding earlier evidence, as I thought I likely had micrometastases for many years, I was greatly encouraged when I saw the paper by Oefelein, Aggarwal, and Resnick (practicing in the Cleveland, Ohio area, at Case Western Reserve University) back in 2004. They were rebutting the “historically reported” conventional consensus that survival after castration resistant prostate cancer (CRPC, then known as HRPC) was only 18 to 24 months. Now we know that there is some time typically between development of CRPC and metastatic disease, so survival after the onset of metastatic disease, such as studied in the CHAARTED trial, would be even shorter — about 30 months median survival for the high-risk group (which had either visceral metastases or ≥4 bone lesions with ≥1 beyond the vertebral bodies and pelvis) on ADT alone in the CHAARTED study, and the median not reached at 60 months for the low-risk group. Yet, in their retrospective chart review, the authors of the 2004 study found that median survival, counted from development of CRPC, was 40 months for patients with skeletal metastases and 68 months for those without skeletal metastases! That was highly encouraging to me as I was responding very well to intermittent triple androgen deprivation therapy (IADT3) at the time — no CRPC in sight for me. Moreover, as this paper was published in April of 2004, these patients had obviously not had the benefit of the wonderful developments we have seen over the past decade and a half. (In contrast the CHAARTED study started in July, 2006.)

    Finally, only 42% (331/790) of these patients had more than 30 days of antiandrogen therapy as part of combined therapy. I am personally convinced that that combination is superior to single agent ADT (LHRH agonist back then — no degarelix yet, or surgical castration available until a decade later). If true, that means that survival would have been enhanced for such patients, and that would add some months to the survival time. I’ll raise that in another post, supported by rough evidence in the first paper.

  6. Dear Jim:

    As long ago as 1989, the standard perception of survival after diagnosis with multiple metastasis to bone and or visceral metastasis for most patients who would have met high-risk criteria as defined in the CHAARTED trial was actually 18 to 36 months, not 18 to 24 months.

    We have long known that survival time varied enormously depending on a whole spectrum of factors.

    The addition of docetaxel-based chemotherapy to ADT in newly diagnosed men with ADT-sensitive prostate cancer has made a large difference to median overall survival in men with high-risk disease … but it has made no meaningful difference to the median overall survival of men with low-risk disease (as defined in the CHAARTED trial).

  7. CLUES IN CHAARTED WHETHER COMBINED ADT IS SUPERIOR TO SINGLE BLOCKADE?

    The complete update of the CHAARTED study is not freely available on the web, but the earlier report gives a tantalizing clue about this important and understudied issue. Figure 2, Hazard Ratios for Death in Subgroups from the initial CHAARTED report (Sweeney et al, http://www.nejm.org/doi/full/10.1056/NEJMoa1503747) provides data on combined ADT (“combined blockade” in the paper, which meant adding an antiandrogen, most likely bicalutamide during this period) versus single ADT (an LHRHR-agonist or surgical castration). As many patients are on an antiandrogen briefly to prevent flare, the authors filtered their data to show only combined ADT patients who were on the combination for more than 30 days, which is at least two weeks more time than would have been used to prevent flare. It is likely the case that the patients on such combined blockade would have been on it for many months or several years.

    Figure 2 shows, for this subgroup in the hazard ratio subgroups tree, that 459 of the 790 total number of patients in the trial were not on combined blockade for more than 30 days, while 331 were on such combined blockade. Those on combined blockade did better, with a lower hazard ratio for death of 0.52 (0.34-0.79), compared to the hazard ratio for those not on combined blockade of 0.69 (0.49-0.99). If that reflects truth, which is the question, from a patient’s perspective that is a rather striking difference: a fifty/fifty chance of dying versus a two-thirds chance!

    However, the key missing parts of this clue whether combined blockade is better are the numbers and proportions of patients in these groups who were at high versus low-risk (as we know low-risk patients are more likely to survive), and the proportions of high-risk patients that received early chemo per the trial protocol versus those who did not, as we know that the high-risk early chemo patients were more likely to survive. In other words, if chance resulted in substantially more high-risk patients getting early chemo and low-risk patients also being on combined blockade, that would suggest a less favorable impact for combined blockade, and vice versa.

    What is encouraging is that it is obvious that these data exist; in other words, patient data with their case and treatment characteristics exist, including whether or not they had more than 30 days of combined blockade, even though this aspect may not have been included in the paper or supplementary data. I am seeking the full current paper through my local medical library.

    I hope it is obvious that I am not looking at these data as proof of the superiority of combined blockade. Even if the data did line up to support the superiority of combined blockade, it would be a secondary analysis with a number of possible confounders. That said, in this inadequately studied area, we may be able to get some clues regarding this issue. This is not an academic question as the extremely high cost of most of the new drugs, plus limitations on their approved “indications,” means that many patients may not be able to afford such drugs but could afford the generic antiandrogens.

  8. Dear Jim:

    Re “I hope it is obvious that I am not looking at these data as proof of the superiority of combined blockade.”

    Good, because, as I keep pointing out, there is extensive data showing a lack of any such benefit (on average) from a number of large trials. And there are significant additional risks associated with long-term antiandrogen therapy.

  9. Follow-up to “jimwaldenfels, on February 20, 2018 at 5:25 pm said:

    CLUES IN CHAARTED WHETHER COMBINED ADT IS SUPERIOR TO SINGLE BLOCKADE?”

    Based on reading the complete copy of the new CHAARTED update, I see that patients were stratified by “planned use of combined androgen blockade for >30 days (yes v no)”. I have found no available database or papers exploring CHAARTED results from the combined blockade perspective, but I am contacting the research team.

    Regarding previous discouraging trial evidence, my survivor’s view is that the devil is in the details. I understand that the preponderance of sound evidence may be against combined blockade, but I suspect that teasing out key details from important studies and viewing results from a fresh perspective will support combined ADT.

    Cheers.

  10. Dear Jim:

    Retrospective analysis of studies to “tease out details” in the way you describe is hypothesis-generating at best. It does not provide “evidence” of anything because the trials weren’t designed to account for such issues.

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