THE "NEW" PROSTATE CANCER INFOLINK

Evolutions in the treatment of nmCRPC

17 Responses

1. tarhoosier, on February 6, 2018 at 9:10 am said:

   I see this in other trials and it always causes me to stop and consider: median duration of treatment is 18.x months, median MFS is 36.x months. What happens in the intervening 18 months? (Statistics in grade 12 was my last experience)
2. Bob Lederer, on February 6, 2018 at 10:12 am said:

   So encouraging for those of us who have just started enzalutamide even if we have metastases. Starting any new treatment is daunting, especially if you read the package inserts. These results make it easier to swallow the pills!
3. Sitemaster, on February 6, 2018 at 11:57 am said:

   Dear Tarhoosier:

   There can be all sorts of reasons why patients come off protocol. Median duration of treatment means median time on the exact and specific protocol to which the patient was assigned. So patients may have come off protocol but still been followed for time to metastasis.
4. Herb Skovronek, on February 6, 2018 at 5:28 pm said:

   Read both abstracts, still unclear what is included in “standard treatment with ADT”: Lupron/Zoladex/Degarelix, Casodex, Avodart? Zytiga/pred?

   I believe there is a selection difference in PSADT, but don’t know if it’s significant.
5. MS Park, MD, on February 6, 2018 at 7:52 pm said:

   We have already very cheap generic antiandrogen, Casodex. And it had confirmed that ADT+casodex has better than ADT alone. So I want to whether ADT+enzalutimide or apalutamide is better than ADT+casodex or not.
6. Sitemaster, on February 7, 2018 at 5:31 am said:

   Dear Herb:

   It definitely did NOT include any treatment with abiraterone acetate (Zytiga) + prednisone. With respect to the others, it probably doesn’t matter if the patiensts all met standard criteria for castration-resistant diease.
7. Sitemaster, on February 7, 2018 at 5:39 am said:

   Dear Dr. Park:

   Treatment with the addition of bicalutamide (Casodex), added after patients progressed on an LHRH agonist or orchiectomy, was tested many, many years ago. It provided up to about 7 months progression-free survival — nothing like the effect shown in these two trials.

   It is also likely that many of the patients in the two trials had already progressed on bicalutamide since the standard definition of castration resistance is a rising PSA while on ADT and after treatment with two forms of standard ADT.
8. maack1, on February 7, 2018 at 11:31 am said:

   The data for both enzalutamide and apalutamide is encouraging. Now we need FDA approval prescribing for nmCRPC rather than only following chemotherapy so that health insurers will provide necessary coverage.

   What is not shown here is what the cost of apalutamide will be compared to enzalutamide. Heath insurers may lean to that which will cost them less regardless that enzalutamide shows a bit more promise and apalutamide may cost less. However, since both IMRT and PBRT are both approved for EBRT with PBRT known to be more costly — and health insurers for the most part will cover PBRT if that is the option chosen by physician and patient — the same may become the case for enzalutamide and apalutamide. Either certainly needs to be considered for non-metastatic, castration-resistant prostate cancer to avoid moving to the toxicity of chemotherapy any earlier than absolutely necessary.

   In reading comments, I was surprised that Dr. Park was not aware of the significant difference in effectiveness of enzalutamide vs bicalutamide in blocking androgen receptors from T/DHT access.
9. MS Park, MD, on February 7, 2018 at 9:20 pm said:

   Dear sitemaster,

   Regarding the inclusion & exclusion criteria, I am not sure that the patients included in this study had antiandrogen treatment.

   Inclusion Criteria:

   Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features;
   Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist or prior bilateral orchiectomy (medical or surgical castration);
   Testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening;
   Progressive disease on androgen deprivation therapy at enrollment;
   PSA and the screening PSA assessed by the central laboratory (central PSA) should be ≥ 2 µg/L (2 ng/mL:
   PSA doubling time ≤ 10 months;
   No prior or present evidence of metastatic disease;
   Asymptomatic prostate cancer;
   Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
   Estimated life expectancy ≥ 12 months.

   Exclusion Criteria:

   Prior cytotoxic chemotherapy;
   Use of hormonal therapy or biologic therapy for prostate cancer (other than approved bone targeting agents and GnRH agonist/antagonist therapy) or use of an investigational agent within 4 weeks of randomization;
   Known or suspected brain metastasis or active leptomeningeal disease;
   History of another invasive cancer within 3 years of randomization;
   Absolute neutrophil count < 1000/μL, platelet count < 100,000/μL, or hemoglobin 2 mg/dL (177 µmol/L) at screening;
   Albumin < 3.0 g/dL (30 g/L) at screening;
   History of seizure or any condition that may predispose to seizure;
   Clinically significant cardiovascular disease;
   Gastrointestinal disorder affecting absorption;
   Major surgery within 4 weeks of randomization;
   Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene;
   Any concurrent disease, infection, or comorbid condition that interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of data, in the opinion of the investigator or medical monitor.
10. Sitemaster, on February 8, 2018 at 11:49 pm said:

    Dear Dr Park:

    Please look at the inclusion criteria that you have listed, where it clearly states:

    “Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist or prior bilateral orchiectomy (medical or surgical castration);
    “Testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening;
    “Progressive disease on androgen deprivation therapy at enrollment;”

    These three criteria are the fundamental defining factors for a patient who has stopped responding to androgen deprivation therapy (ADT).

    I can assure you with 100% certainty that these patients had all been treated with and were no longer responding to ADT.
11. MS Park, MD, on February 11, 2018 at 8:27 pm said:

    Dear Sitemaster:

    Androgen deprivation therapy (ADT) is a treatment that lowers testosterone to castrate level. As described in the inclusion criteria, PROSPER trial defined it as GnRH agonist/antagonist or orchiectomy.

    We call ADT plus antiandrogen (Casodex) as combination or maximal androgen blockage, not ADT.

    I can not find the text that clearly defined these patient took antiandrogen or not. If you have, it will be great help.

    I found that SPARTAN trial included the patients who treated with previous first-generation antiandrogens with 4-week washout periods.
12. Sitemaster, on February 12, 2018 at 8:35 am said:

    Dear Dr. Park:

    There are numerous forms of ADT, inclusive of so-called “combination” or “maximal” ADT. However, an extensive series of clinical trials between 1990 and about 2000 provided compelling data that the combination of an LHRH agonist (also known as a GnRH agonist) with a first-generation antiandrogen (flutamide, nilutamide, or bicalutamide) had value in stopping the initial “flare” reaction associated with initiation of LHRH agonist therapy but little to no real long-term survival benefit in most situations (see below).

    We also know that: (1) when men initially progress after an orchiectomy or on treatment with an LHRH agonist, addition of a first-generation antiandrogen can lower their PSA level for a matter of a few months (in most cases); (2) when they again progress on the combination of an LHRH agonist or orchiectomy + a first generation antiandrogen, withdrawal of the antiandrogen can again lower PSA levels for a matter of a few months — the antiandrogen withdrawal effect. However, neither of these actions has ever been shown to have a long-term survival benefit.

    In most of the world, as far as I am aware, there is limited use of maximal androgen deprivation today because of these findings. However, I will agree with what you are implying, which is that men whose serum testosterone (T) and serum dihydrotestosterone (DHT) levels are dropped to very low levels (e.g., men with a serum T level of < 20 ng/dl) appear to have better long-term outcomes than men who only have a serum T level of < 50 ng/dl.

    There has never been any large, randomized clinical trial that carefully measured patients' serum T or serum DHT levels over time and correlated that information to their treatment to prove that a specific form of treatment that achieved lower serum T or serum DHT levels was "better" at extending the patients' overall survival.

    If you look at Table 1 in the full publication of the data from the SPARTAN trial (by Smith et al.), you will see that > 71% of men in this trial had received treatment with a first-generation antiandrogen. The table doesn’t tell us how long for or when they received such therapy, however. The fact that such patients underwent a 4-week washout period if they were on an antiandrogen at the time of enrollment makes perfect sense to me. If they hadn’t then we wouldn’t have been comparing apples to apples.

    I would also repeat what I told you previously. There has never been any inkling of a suggestion that men treated with maximal ADT (as opposed to standard ADT and then the addition of an antiandrogen at initial progression) could produce an overall survival benefit of more than 7 months (as originally suggested by Crawford et al. in 1989). And that 7-month survival benefit was never repeated in any other trial of maximal ADT (see for example Eisenberger et al. in 1998). Nor has use of any first-generation antiandrogen in association with surgical or medical castration ever been associated with any delay in time to metastasis in men with non-metastatic, castration-resistant prostate cancer (nmCRPC).

    By contrast, the use of apalutamide in the SPARTAN trial and of enzalutamide in the PROSPER trial have both shown an enormous improvement (of c. 40 months) in time to onset of metastatic disease in men with nmCRPC. But … in neither trial is there (as yet) any clear evidence of an overall survival benefit.

    There is very little doubt that: (1) we are still learning about “the best” ways to treat men with progressive forms of prostate cancer; (2) there is enormous variation from patient to patient in how individuals with prostate cancer respond to differing types of therapy; (3) we still have very little understanding about “the best” time to start most patients on any and all types of androgen deprivation therapy.

    What the SPARTAN trial and the PROSPER trial have done is show that apalutimide and enzalutamide are much more active in men with nmCRPC than the first-generation antagonists ever are. Whether it is appropriate to start all patients on these drugs when they first become castration-resistant is going to be a whole other question. The cost would be enormous.
13. MS Park, MD, on February 12, 2018 at 7:42 pm said:

    Dear Sitemastrer:

    Thank you for your kind explanation. I agree with you regarding the difference btw 1st and 2nd generation antiandrogen, which is proved by head-to-head study “STRIVE Trial”. What I want to sure was the detailed design of PROSPER trial.

    I think the enzalutamide is one of the antiandrogen that competitively inhibit the androgen receptor as Casodex. Better antiandrogen, not a totally different mechanism. And it show resistance also. I expect the indication of 2nd generation antiandrogen will be same as 1st generation if price come down.

    Anyway, I thank again you and this site to give new and digested information that is very valuable for me and my patients.
14. jimwaldenfels, on February 17, 2018 at 4:56 pm said:

    Combined blockade (LHRH-agonist plus antiandrogen) versus LHRH-agonist alone

    First, thanks to Sitemaster for this great reporting, and to earlier commenters. (Hi Chuck!)

    I’m now at the 18-year-plus point since I started ADT back in December 1999, so my memory of the trial evidence I was looking at in those early months is a bit fuzzy, and I haven’t done a PubMed search. But I, as a patient who had my life on the line, remain impressed that combined blockade is a better choice.

    My recollection is that a number of prominent oncology practices dedicated to prostate cancer patients were seeing marked differences in results between patients on an LHRH agonist only (with the LHRH antagonist degarelix not to be available for more than a decade) versus those with on an LHRH agonist plus an antiandrogen. I recall slide shows that sure made the combo appear the more effective option! At least some, perhaps most, of the studies in the slide shows were clinical series reported by prominent practices rather than clinical trials, and, of course, such evidence is not as convincing as a large, randomized, double-blind clinical trial. Thus, it is quite possible that what I recall and what Sitemaster summarized about the research (no impressive advantage for combined blockade) are not inconsistent.

    I would like to see a thorough review of the evidence, but doubt that that has been or will be done, especially now that superior forms of antiandrogen are available, as well as superior forms of suppressing testicular testosterone. However, if someone were to look back, one critical detail is the dosing of the antiandrogen. I was always on a low, 50 mg daily dose (as I had no evidence of metastasis except for one doubtful, pinhead-sized spot in an unlikely area for an early metastasis), but higher-risk patients were routinely on a dose of 150 mg daily in the practices whose results I followed. (In fact, even higher doses in one prominent practice.) Yet I’ll bet some of the research that failed to show much impact of combined blockade used the lower dose, even if the patient was at higher risk. It is well known that flutamide and bicalutamide do not bind as well to androgen receptor as we would like, and therefore higher doses could make quite a difference, overcoming deficiencies in binding with greater numbers, while the lower dose tactic could be a formula for failure.

    There is some relevance to rethinking the use of bicalutamide as it is now a fairly inexpensive generic. (It used to cost between $13 and $17 per pill.) Thus, there is a great cost saving if a patient can be managed well with a strategy involving bicalutamide rather than one of the potent but high-priced antiandrogens, either Xtandi or Erleada.

    (My therapy became intermittent triple ADT — specifically Lupron, bicalutamide (until the final round where a possible androgen receptor mutation made flutamide the better choice), and finasteride for most years but dutasteride in latter years. On this regimen I was able to drive my PSA from a baseline of 113.6 with a flare to 125 to less than 0.01 for the first two rounds, 0.02 for the third, and 0.02 for the fourth at the end of 18 months of ADT3 in support of IMRT Tomotherapy a year earlier. Now, virtually 5 years after completing radiation, my PSA has never been higher than < 0.05. remain on dutasteride three times a week as part of my safety net against a recurrence.)
15. Sitemaster, on February 18, 2018 at 9:56 am said:

    Dear Jim:

    I would remind you that the FDA refused to approve the use of 150 mg of bicalutamide in the US because of serious concerns about the side effects observed in US-based patients in the relevant pivotal trials. The side effects were less evident in European patients in those trials (which was why the 150 mg dose was approved in Europe but not in America).

    The “first-generation” antiandrogens all came (and still come) with a spectrum of side effects which, when added to the side effects we are familiar with from treatment with an LHRH agonist, meant that — for many patients — the risk/benefit equation was significantly shifted further into the risk spectrum (although of course there have always been individual patients for whom the benefit outweighed the risk).

    You need to appreciate that there is no way any physician can tell in advance whether a specific patient will have more risk or more benefit from the use of combined or maximal androgen deprivation (CAD/MAD) when he is started on and then maintained on such therapy. The primary reason why most physicians defaulted to only 2 weeks of an antiandrogen (to prevent flare) and then LHRH agonist monotherapy is because of the simple guidance “first do no harm” that is implicit in the Hippocratic Oath. There are no compelling data to show a meaningful survival benefit from CAD/MAD from randomized clinical trials.
16. jimwaldenfels, on February 18, 2018 at 4:33 pm said:

    Casodex at 150 mg — trials and safety considerations

    Sitemaster — thank you as always for replying (9:56 am).

    Many of us who were making treatment choices learned a long time ago that antiandrogen monotherapy was not as effective as other choices, especially those involving an LHRH agonist, which was the main alternative back then. It appears that the clinical trials leading to non-approval of the 150 mg dose involved only monotherapy use. The doctors I have followed have used the higher dose, off-label in the US, in conjunction with suppression of testicular androgen, which was by surgical castration or an LHRH-agonist years ago. Unfortunately, it appears that no Phase III trials have been done (judging by the FDA approval document) for combined therapy with the higher dose.

    The major safety issue for all of us is liver function. While the percentage of patients adversely affected is quite small, if an adverse impact on the liver is not detected, the result is serious, often fatal. Fortunately, as all of us probably know, liver function tests during the early months of treatment are effective at spotlighting this issue, and later routine monitoring of blood and symptoms can detect subtle issues, as I understand it. Moreover, certain medications, such as ursodiol, have been used both to forestall liver problems and to help some patients with the liver issue to safely take an antiandrogen.

    What this all means is that it is possible for a physician to do timely monitoring to ensure that the antiandrogen (bicalutamide, flutamide) can be given safely to a patient or ruled out for a patient.

    However, I suspect that many physicians are not aware of ways of effective management of patients starting one of these antiandrogens, and therefore the risk/benefit ratio would be daunting. It is understandable that such physicians would not do off-label prescribing.
17. Sitemaster, on February 20, 2018 at 10:12 am said:

    Dear Jim:

    Respectfully, the fact that “the doctors you have followed” have been using combinations of 150 mg of bicalutamide + an LHRH agonist off-label does not necessarily make it a good idea at all. Most experts in this field would not make such a recommendation — for all sorts of reasons. And I can tell you that if I had progressive prostate cancer that required ADT, I would certainly not consider such an option outside a well-defined clinical trial.

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