ARCHES study data reported in JCO, and related issues


The initial data from the ARCHES study of standard ADT + enzalutamide versus standard ADT + a placebo in men with metastatic, hormone-sensitive prostate cancer were reported earlier this year at the Genitourinary Cancers Symposium in San Francisco. However, the detailed study data, indicating a 61 percent improvement in radiographic progression-free survival among men in the standard ADT + enzalutamide arm of the trial, have just been published by Armstrong et al. in the Journal of Clinical Oncology.

The full text of the article by Armstrong and his colleagues is freely available to all interested readers on line.

What we still do not know is whether the combination of standard ADT + enzalutamide in treatment of men with mHSPC improves the overall survival of such men over time compared to just giving that ADT + a placebo (with the potential for use of enzalutamide later on).

We now have a total of four “second generation” forms of androgen deprivation therapy that have been shown to be effective in the treatment of “hormone-sensitive” and/or “castration-resistant” forms of prostate cancer when added to standard forms of ADT:

  • Darolutamide is effective in the treatment of men with high-risk nmCRPC, based on data from the ARAMIS trial (but has not yet been approved for use in this indication by the US FDA)
  • Apalutamide (Erleada) is effective in the treatment of men with non-metastatic, castration-resistant prostate cancer (nmCRPC), based on data from the SPARTAN trial
  • Enzalutamide (Xtandi) is effective in the treatment of men with
    • mHSPC, based on data from the ARCHES trial (but it has not yet been approved for use in this indication by the US FDA)
    • nmCRPC, based on data from the PROSPER trial (but it has also not yet been approved for use in this indication by the US FDA)
    • mCRPC, either before or after treatment with docetaxel-based chemotherapy, and has been approved by the US FDA for this use
  • Abiraterone acetate (Zytiga) is effective in the treatment of men with
    • “High risk” mHSPC based on data from the LATITUDE trial, and has been approved by the FDA for this use
    • mCRPC, either before or after treatment with docetaxel-based chemotherapy, and has been approved by the FDA for this use

And, of course, we also have data from the STAMPEDE trial showing that the combination of standard ADT + abiraterone acetate is an effective form of treatment for newly diagnosed patients with mCRPC as well. However, this trial contained patients in both high and low risk groups and so its interpretation is a little more complex (see here).

It seems very reasonable to think that enzalutamide and darolutamide will gain approvals for their all their unapproved uses indicated above some time between now and the end of 2019.

The point that patients need to appreciate here is that the actual appropriate order of use of these agents, and which is “best” in any specific scenario is still largely undetermined. This is the sort of topic that will get addressed in some detail at the upcoming meeting of the Advanced Prostate Cancer Consensus Conference in Basel in August (as mentioned in yesterday’s post). For practicing urologists and medical oncologists, the precise and most appropriate uses of these four drugs in the various patient types is currently very hard to determine with a high degree of accuracy.

The other great unanswered question today is whether one or more of these drugs could be used early, effectively, and safely in the treatment of advanced and high-risk forms of prostate cancer without concomitant use of a standard form of androgen deprivation therapy (i.e., an orchiectomy or medical castration with an LHRH agonist or antagonist). It will take time to work this out, and one of the key questions will be whether one could use standard forms of ADT effectively and safely after a patient has progressed on one of the “second generation” of androgen deprivation therapies.

7 Responses

  1. I have been on enzalutamide + sipuleucel-T since 12-25-2015, and in the last 6 months have experienced a small but steady rise in PSA since 04-2019, so I am desperate to try apalutamide or some other form of second/third generation ADT.

    I have also had a subcapsular orchiectomy.

    What I don’t want is chemotherapy out of concern that it my create a worse mutation that may be harder to treat.

    Please, advise: 1-408-840-6694 or dykedavis@gmail.com.

  2. I guess I am in the process of working out the answer to your last question, Mike.

    In an article recently published in the on line journal Oncogen, Don Wheeler and I presented my rationale for choosing Erleada as a monotherapy after my PSA reached a nadir of 5 ng/ml while my serum T levels were still below castrate values. I had previously been treated with Provenge and I hoped that its residual effects plus the standard dose of 240 mg of Erleada would be effective. It was for nearly a year, and in fact my PSA went as low as 0.05 ng/ ml while my T levels were consistently at about 450 ng/dL, i.e., at about double my levels before my Gleason 9 (5 + 4) cancer was diagnosed in June 2014.

    After the Oncogen article was published, my oncologist and I attempted a dose reduction of Erleada to 120 mg daily to see if that might reduce some side effects I was experiencing (fatigue, joint pain, and motor neuropathy) while Provenge picked up the slack, so to speak. The first month at 120 mg saw no change but subsequently my PSA started to double again at its usual rate after failed treatments, even after we restored Erleada to its full dose.

    My latest PSA was still numerically low (0.42 ng/ ml) and my T level was still above 450.

    At my next consultation in 10 days we will explore alternatives to returning to chemical castration via Firmagon.

    I don’t regret my decisions to try Erleada as a monotherapy or to attempt the dose reduction.

    I completed 3 professional papers I had been trying to put the finishing touches on for years while I was taking only Erleada and I have an extensive treatment history I can draw on in planning the next step in my journey with prostate cancer.

    Thinking outside of the box has provided me with experiences to share with others and I thank you for letting me do this using your platform.

    I hope this comment stimulates others to reply who either have or are contemplating taking Erleada as a monotherapy.

    I will write up my results for submission to Oncogen when I decide on a course of action because I think we learn as much by these single case studies as we do from the large-scale group comparison designs, particularly during the early stages of investigating a medication’s effects when results from those studies will not be available to help others who are faced with decisions they must make right now based on the best available evidence.

  3. What is hormone-sensitive, metastatic prostate cancer? Does it refer to patients who have never been treated with androgen deprivation like Lupron, or, does it mean patients who are on ADT with metastatic disease that has not progressed while on ADT? or, both? if patients with metastatic disease who have not progressed are included in this category — for how long have they not progressed to be considered hormone sensitive? I am not sure which patients were included in the ARCHES, study as I do not clearly understand who are considered hormone-sensitive patients with metastatic disease. Thanks in advance.

    Rob

  4. Dear Mr. Davis:

    This is really an issue you need to discuss with your doctors. There are numerous factors that might affect exactly when you need a new form of treatment and what that treatment should be if you choose to avoid chemotherapy. However, you should also be aware that “worse mutations” can occur for all sorts of reasons during the progression of prostate cancer, and many of these occur in men who don’t have chemotherapy at all.

    One thing you should probably discuss with your doctors is the need for appropriate genetic testing to see exactly what mutations have already occurred (if you have not had such “next generation” genetic testing done to date). The results of such testing might help your doctors to determine a new form of treatment that might be the most appropriate for you.

  5. Dear Rob:

    Strictly speaking, man who has metastatic, hormone-sensitive prostate cancer is a man who has (a) been diagnosed with metastatic prostate cancer; (b) has been treated with a standard form of ADT (e.g., orchictomy or medical castration using an LHRH agonist); and (c) has shown no signs of disease progression after starting such therapy (i.e., his PSA level has dropped to a very low level and his disease appears to have stabilized) — for whatever period of time (3 months or 10 years).

    The term sometimes can be used to also include men who have just been diagnosed with metastatic prostate cancer and are expected to start treatment with some form of standard ADT. However, strictly speaking such men should really be defined as having metastatic, hormone-naive or metastatic, ADT-naive prostate cancer.

    The types of patients who were eligible for inclusion in the ARCHES trial are listed in some detail in the paper by Armstrong et al., as follows:

    “Eligible patients were adult (defined according to local regulation) males with pathologically confirmed prostate adenocarcinoma, without neuroendocrine differentiation, signet-cell, or small-cell features, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Eligible patients had hormone-sensitive metastatic disease, either de novo or after recurrence after prior local therapy, documented by a positive bone scan, or metastatic lesions on computed tomography or magnetic resonance imaging. Enrollment was based on investigator-assessed metastases; after study entry, metastasis was evaluated by independent central review. Prior ADT and up to six cycles of prior docetaxel chemotherapy were permitted. Patients who experienced disease progression prior to randomization while receiving ADT and/or docetaxel were excluded. Additional details regarding inclusion/exclusion criteria are provided in the Data Supplement.”

    You can also review the eligibility criteria in the description of the trial on the ClinicalTrials.gov web site.

  6. Do you know if there will be initial results of the EMBARK trial soon?

  7. Dear George:

    The estimated primary completion date for the EMBARK study is in July 2020 (see here). That is the estimated date for the primary study endpoint. The full trial won’t be completed until some time in 2023.

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