Should you be adding abiraterone acetate to your ADT? — Part II


So one of the benefits of being at the annual ASCO meeting is that you get to talk to lots of medical oncologists who specialize in treating prostate cancer — if you are patient and polite.

Your sitemaster therefore took the opportunity to ask several of them, earlier today, what they would recommend in the following situation:

A 69-year-old patient was diagnosed a year ago with a PSA of 50 ng/ml, a Gleason score of 8, and two small foci of metastatic prostate cancer — one in his right hip bone and the other in his right shoulder. He had no pain at the time of diagnosis. He had been treated with simple ADT, to which he had responded well and his PSA was virtually undetectable. However, the patient had seen the reports from the ASCO meeting on the data from the LATITUDE and the STAMPEDE trials. Next Monday, when the oncologist returned to his practice after ASCO, the patient was waiting for him and asks, “Don’t the data from these two trials suggest that I should start on abiraterone immediately, while staying on the ADT?”

Your sitemaster was not at all surprised to get several different responses to this question, and he would emphasize that every one of the specialists included a statement that the best decision would depend on the precise details of the diagnosis of the individual patient and other health factors, but here is the spectrum of responses:

  • Yes, assuming that I could get the patient’s insurer to cover the cost, I would immediately add abiraterone to his ADT. This is a patient with a high potential for a long life expectancy and aggressive treatment like this ought to optimize his life expectancy based on the data presented at the meeting.
  • No. This patient is well controlled on ADT. If I was going to do anything with this patient it would be to talk to him about targeted radiation therapy to the two sites of metastatic disease and simply maintaining him on the ADT. We have no data from the trials presented at ASCO to suggest that adding on abiraterone later in such a patient would have the same effect as shown in the newly diagnosed patients who were started on the combination therapy immediately. I would want to reserve abiraterone for later use in this patient (i.e., when he started to show signs of castration resistance).
  • No. These data haven’t been evaluated yet by either the FDA or the NCCN or any other body responsible for clinical guidelines. And there are real questions about whether adding abiraterone on later in patients who are already on ADT would be beneficial. All these data need very careful consideration before we start making real decisions about how to apply them — particularly how one might be able to apply them outside of the very specific uses described in the two clinical trials.
  • No. Not immediately. What I would do with this patient is keep him on ADT for a while longer. If his PSA remained virtually undetectable, I would then stop the ADT and simply monitor his PSA to see whether it started to rise again (intermittent ADT). If and when that happened, then I would want to try re-starting him on the combination of ADT + abiraterone — as if he was a newly diagnosed patient with metastatic disease.

You will see that I have deliberately not included the names of the physicians I spoke to. I did not have a recorder with me and so what you have above is the “flavor” of the different responses as opposed to the absolute quotations.

The point that I would make to readers who are trying to understand the possible relevance of these new data from LATITUDE and STAMPEDE to their individual situations is that it may take a while to sort this out. What is clear at this time is that we now have two effective options for the treatment of men newly diagnosed with either high-risk M0 or M1 prostate cancer: ADT + abiraterone and ADT + docetaxel chemotherapy. Exactly which of these types of therapy may be most appropriate in an individual patient is going to be a matter for discussion and careful clinical evaluation. They each have upsides and downsides.

There is also still another unanswered question — raised by Dr. Johann de Bono during a discussion session late yesterday: Do we now know whether early androgen deprivation therapy is better and provides a longer survival benefit (albeit with more side effects and other potential complications) than delayed androgen deprivation therapy? The answer to that question remains … No, we don’t.

And last but by no means least, the full texts of the two articles giving the results of both the LATITUDE trial and the STAMPEDE trial are now both available on line, prior to full publication, on the New England Journal of Medicine web site. You can therefore read them for yourselves.

6 Responses

  1. You guys are right on with your timely assessment of the importance of this latest research. We have much still to learn from this encouraging development. Thanks for all you do.

  2. Good question and interesting (and not surprising) answers. On a related note, how does one find these MOs who specialize in prostate cancer?

    Bob

  3. This site rocks. Just for the record.

  4. Many of them are the ones who are regularly involved in the types of trials of new drugs that we report on.

  5. Other Issues and Tactics Worth Consideration Before Moving to Abiraterone

    As always, thanks Sitemaster for helping us think about these issues.
    There are some other issues and tactics worth consideration before moving to abiraterone, and it’s interesting that these were not mentioned by the oncologists you interviewed. Perhaps that was because they were focusing on the prospect for using abiraterone; I can see myself doing that in a conference interview situation. Here are some issues and tactics that come to mind for the Gleason 8/high PSA patient with two detected metastases but no pain at diagnosis and an apparently good ADT response in your scenario.

    DEBULKING: The scenario indicates the patient’s prostate has not been treated for cancer, an approach known as “debulking”. Debulking may be controversial for an advanced patient with metastatic disease, but some highly respected doctors who treat prostate cancer consider it a key part of their treatment. One of them is Dr. Nick Vogelzang, very well known as a leading director of clinical trials, who addressed this as the second of his six key “principles for the evolving solution” for patients with challenging cases. He stated that surgery or radiation for the primary cancer [meaning in and around the prostate] is always a component of the cure. (2016 Conference on Prostate Cancer, DVD disc 2, 1:16:09) Dr. Charles “Snuffy” Myers, another conference speaker, echoed the importance of debulking the primary cancer during his Q&A Meet the Speaker session: “a standard of our approach.” (Disc 4: 3:06:33).

    IMAGING, AND POSSIBLE TREATMENT OF OLIGOMETASTATIC CANCER: It is not clear whether the patient had modern sensitive imaging or relatively insensitive imaging such as the technetium (Tc) bone scan and a CT scan for soft tissue. Far more sensitive scans exist, such as the NaF18 PET/CT scan for bone and C-11 acetate or choline PET/CT scans, and PSMA based scans, for soft tissue (as well as partly for bone). While the patient’s current PSA is likely indicating the cancer is too small to be picked up by the soft tissue scans, if the advanced scans were the original source of the information on the metastases, then the patient would probably be a candidate for surgery or spot radiation to wipe out what would appear to be oligometastatic cancer.

    TYPE OF PSA TEST USED: What does “virtually undetectable” mean? Some doctors still use <.1 as undetectable, perhaps even for advanced patients, but this patient should be tested with ultrasensitive PSAs with a lower limit of <0.01 according to a number of doctors with large practices dedicated to prostate cancer with heavy proportions of patients with advanced and challenging cases. If the patient’s PSA was not 0.05 or below after a year on “simple” ADT, they would definitely want to add other therapeutic tactics. I’ve seen the use of ultrasensitive testing for ADT patients (and others) grow over the years since 2000, and perhaps that is now the standard of care for oncologists at the ASCO conference and the reason for no comments.

    TYPE OF ADT USED: The patient has been treated with “simple” ADT, probably meaning just an LHRH-agonist (or orchiectomy). Doctors dedicated to PC whom I follow would want this patient to have a PSA of at most <0.05, and preferably <0.01, and if not they would use other ADT tactics beyond “simple ADT”, though perhaps they would stick with that if it had proven sufficient for the patient to get at most down to <0.05. The first tactic would likely be to add 150 mg of Casodex daily (higher dose because metastatic – I was always on 50 mg), but they might try to get insurance coverage for Xtandi instead because Xtandi is far superior at binding to the androgen receptor fuel ports for the cancer. They would also be testing for DHT, and if it were greater than 5 would likely add Avodart/dutasteride (a 5-alpha reductase inhibitor), to crush conversion of any remaining testosterone to DHT, which is a far more potent fuel for the cancer than testosterone), switching to Proscar/finasteride if DHT failed to fall sufficiently, indicating a genetic problem. Use of combinations of drugs was the first of the key principles on Dr. Vogelzang’s list: “Cure of childhood leukemia required at least 8 drugs. Hodgkins disease requires at least 4. Testicular requires 3. All the therapies that we use require more than one drug. [I think he meant curative drug therapies.] All are built upon effective single agents that can be combined simultaneously and used repetively.” (Disc 2, 1:15:32) While he was addressing curative therapy attempts, I suspect he would apply that to ADT as well, as do a number of prominent doctors with large practices dedicated to prostate cancer.

    COST ASPECT: Abiraterone is far more expensive than the generic drugs above (not including Xtandi, which is not available as a generic and is expensive), and its unnecessary use would result in some “financial toxicity.”

    GENETIC TESTING FOR BRCA2 AND ATM, PERHAPS OTHERS, BEFORE USING ABIRATERONE. The following paper with an author list including a number of prominent prostate cancer oncologists (including Dr. de Bono as the senior author), indicates that certain genetic mutations decrease the likelihood that abiraterone will work, but that the drug olaparib (Lynparza) can target those mutations and enable abiraterone to work: N Engl J Med. 2015 Oct 29;373(18):1697-708. doi: 10.1056/NEJMoa1506859.
    DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. Mateo J1, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, Nava Rodrigues D, Robinson D, Omlin A, Tunariu N, Boysen G, Porta N, Flohr P, Gillman A, Figueiredo I, Paulding C, Seed G, Jain S, Ralph C, Protheroe A, Hussain S, Jones R, Elliott T, McGovern U, Bianchini D, Goodall J, Zafeiriou Z, Williamson CT, Ferraldeschi R, Riisnaes R, Ebbs B, Fowler G, Roda D, Yuan W, Wu YM, Cao X, Brough R, Pemberton H, A'Hern R, Swain A, Kunju LP, Eeles R, Attard G, Lord CJ, Ashworth A, Rubin MA, Knudsen KE, Feng FY, Chinnaiyan AM, Hall E, de Bono JS. https://www.ncbi.nlm.nih.gov/pubmed/26510020

  6. Dear Jim:

    With the greatest respect, I think you are rather missing the point of the hypothetical question being asked by this hypothetical patient. There are probably about 30 different ways that one could consider managing such a patient, but the hypothetical question wasn’t, “What’s the best way to manage me?” (which is an unanswerable question anyway). It was a very straightforward one: “Shouldn’t I be getting abiraterone added to the ADT I am already on?”

    To pick the simplest of your comments, it would certainly have been reasonable to debulk this man’s tumor prior to or in conjunction with initiation of the ADT. It wasn’t done. I don’t know why not because it is a hypothetical patient, but maybe he just didn’t want to do that! I hope you would be among the first to agree that patients’ decisions about how they want to get treated are sacrosanct … even when they aren’t necessarily very good decisions.

    The issues you raise arguably (ans ideally) reflect issues that should already have been resolved before this patient was ever put on ADT and/or after he has a rising PSA on ADT, but they are irrelevant to the hypothetical question he was asking about his personal (and potentially very common) situation. Most patients simply aren’t living in the world you live in.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

w

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.

%d bloggers like this: