What is standard, first-line therapy for men with mHSPC today?

A presentation at the ongoing annual meeting of the European  Society of Medical Oncology (ESMO), in Madrid, Spain, has offered us data comparing abiraterone acetate + prednisone + ADT to docetaxel + ADT in the treatment of men with high-risk, metastatic, hormone-sensitive prostate cancer (mHSPC).

Feyerabend at al. were able to use existing data from the CHAARTED, GETUG-AFU, STAMPEDE, and LATITUDE trials to make this comparison, so what we have are data from an indirect comparison as opposed to data from a direct, randomized, head-to-head trial. However, the available data are, at least, intellectually interesting, and are as reported on the UroToday web site by Zachary Klaassen, MD.

The CHAARTED, GETUG-AFU, and STAMPEDE trials all included sets of patients who were diagnosed with mHSPC and randomized to treatment with either androgen deprivation therapy (ADT) alone or to ADT + docetaxel-based chemotherapy (and based on data from those trials, most guidelines now encourage the use of the combination of ADT + docetaxel-based chemotherapy in the first-line treatment of mHRPC (and especially men with high-risk forms of mHSPC). The LATITUDE and the STAMPEDE trials both included sets of patients who were diagnosed with mHSPC and  randomized to either ADT alone or to ADT + abiraterone acetate + predisone.

What Feyerabend et al. have been able to do is use data from men with high-risk mHSPC enrolled in these trials to offer an  in direct comparison of the outcomes of the men treated with ADT + docetaxel-based chemotherapy to the men treated with ADT + abiraterone acetate + predisone.

According to their analysis, they were able to show that:

  • ADT + abiraterone acetate + prednisone had better suggested outcomes for overall survival than ADT + docetaxel (hazard ratio [HR] = 0.84).
  • ADT + abiraterone acetate + prednisone had better suggested outcomes for radiographic, progression-free survival than ADT + docetaxel (HR = 0.73).
  • These results were consistent (albeit not always statistically significant) across all sensitivity analyses.

The authors apparently concluded that treatment with ADT + abiraterone acetate  + predisone induced a greater reduction in risk of progression and death vs ADT + docetaxel.

With abiraterone acetate (Zytiga) having lost patent protection in many countries (or to lose patent protection shortly), the cost of this form of therapy is not going to be as problematic as it has been in the past, and so we may well see ADT + abiraterone + prednisone become the “standard” form of first-line therapy for high-risk mHSPC in the not-to-distant future. Whether this form of therapy will be as appropriate for men with lower-risk forms of mHSPC (i.e., men with small amounts of metastatic disease and more slowly rising PSA levels) is harder to predict.

4 Responses

  1. This is one of those analyses that I’m inclined to wait to see the peer-reviewed, full-text version. The authors of STAMPEDE cautioned against comparing the two (docetaxel and abiraterone) because the sample sets were different — the docetaxel group seemed to be more progressed with their disease at the outset.

    The criticism of GETUG-AFU-15 (which showed no survival benefit to early docetaxel) has always been that the patient group had more advanced prostate cancerC than those in CHAARTED or STAMPEDE. CHAARTED showed no benefit to early docetaxel among the subset who had a low volume of metastasis (i.e., less progressed). It seems likely to me that those diagnosed with low volume of metastasis are better off starting with abiraterone and those with high volume of metastasis are better off starting with docetaxel (or both). Complicating this still further is the possibility that docetaxel may be able, in some cases, to reverse resistance to abiraterone caused by the AR-V7 splice variant. This really cries out for a randomized sequencing (or simultaneous use) trial.

  2. Thanks for this posting, Mike. I read it just after I submitted my post to the advocacy discussion but it illustrates one of the points I was trying to make.

    What is an individual patient to make of this finding as far as it pertains to his prostate cancer?

    Well, first of all it would seem to depend on whether or not he still has a prostate! I take it to mean that “first-line treatment” means that metastatic disease had been identified before either prostatectomy or radiation treatment had been considered. How is ” high risk” status determined in those cases?

    Presumably, on the basis of an MRI-guided biopsy to obtain a Gleason score or perhaps by applying one of the other algorithms to rank the aggressiveness of the cancer.

    Were treatment results analyzed both within and across these risk stratifications?

    The analysis focused on comparing two combinations of treatment. How does this compare with applying each treatment sequentially?

    Surgeons are now more willing to perform “salvage” prostatectomies after failed radiation treatments. What about this treatment option before starting either ADT or Zytiga?

    Furthermore, were genomic studies done to identify possible likely non- responders to ADT?

    See what I mean about the lack of relevance of the types of studies for making patient-specific decisions?

  3. Dear pfadtag:

    With respect, I think you are missing the point of the heading that was given to this piece, which asked, “What is standard first-line therapy for men with mHSPC today?”

    The answer is: “We don’t know. It all depends.”

    A man who needs “first-line therapy for mHSPC” is a man who might be newly diagnosed with metastatic disease or a man who has failed surgery and/or radiation therapy and is now metastatic but never had ADT until the first clear evidence of metastasis. Any one of multiple types of patient might fit the mHSPC definition.

    If there was “a point” to this piece, it is actually about the problems of “more knowledge”. We used to know exactly what to do with a patient who had mHSPC. He would be given some form of ADT (and the discussion was “only” about exactly what type and exactly when). Today, we really aren’t sure at all. And, in the vast majority of cases, genomic testing and “personalized” forms of medicine can’t yet actually give us any truly beneficial insights either — so both physicians (how ever expert) and patients are having to guess at what “the right” thing to do is for any one particular patient.

    We have more knowledge … but it hasn’t yet helped us to reliably provide better CARE.

  4. I think if you read both posts more carefully you will see that we are on the same page.

    In quality improvement circles we use the term DRIP to refer to the situation where we are Data Rich but Information Poor.

    We have lots of discrete findings in the prostate cancer community but no commonly accepted framework to integrate them.

    We can’t even agree on whether the primary objective of research and treatment should be to find a “cure” or to develop empirically driven treatment algorithms that sustain durable remissions from a chronic condition with minimal side effects.

    The mechanistic medical model of disease has been co-opted by big pharma, the FDA, and greedy insurance companies with the result that patient care has been seriously compromised.

    Case in point … as someone who has failed two front-line attempts to “cure” my prostate cancer which clearly has metastasized somewhere, I am not considered eligible for a trial with Xofigo until I fail to respond to ADT, which I almost certainly will at some point.

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