Improving survival among men with oligorecurrent prostate cancer?


A newly published article in the Journal of Clinical Oncology reports data from a small, randomized, multicenter, Phase II clinical trial comparing active monitoring to treatment of men with recurrent, asymptomatic, oligometastatic prostate cancer.

We have known for a while that there seems to be at least a progression-free survival (PFS) benefit when men with small amounts of “oligorecurrent” metastatic prostate cancer get early, targeted treatment for such recurrence.

What do we mean by “oligorecurrent” metastatic prostate cancer? This is prostate cancer that has recurred after primary first-line therapy (most commonly surgery or radiation therapy) given with curative intent. The patient will have a rising PSA level and will also have early evidence of metastatic disease in the lymph nodes or elsewhere (but not to the brain) at time of disease recurrence.

A group of Dutch researchers (Ost et al.) have now reported data from a small, randomized, clinical trial confirming that targeted treatment of the oligometastases, without the use of androgen deprivation therapy, does indeed seem to be associated with a significant PFS benefit.

Ost et al. enrolled patients who met very specific criteria into this trial. The patients had to have

  • Biochemical recurrence after primary treatment for prostate cancer with curative intent
  • A maximum of three extracranial metastatic lesions on a choline-11 PET/CT scan (i.e., no metastases to the brain)
  • A serum testosterone level of > 50 ng/ml
  • Asymptomatic disease (i.e., no bone pain or other symptoms of metastatic disease)

The patients were then randomized to either

  • Careful surveillance/monitoring (with PSA tests every 3 months and repeated scans as needed based on evidence of risk for progression) but no initial treatment of any type or
  • Immediate metastasis-directed treatment (MTD) to the oligometastatic lesions — using either surgery or stereotactic body radiation therapy (SBRT)

The patients were also stratified based on whether they had: (a) nodal as opposed to truly metastatic (non-nodal) foci of metastatic disease and (b) a PSA doubling time of ≤ 3 months or > 3 months.

The primary endpoint for the trial was ADT-free survival, and ADT might be started for any one of the following reasons:

  • Symptomatic progression (i.e., bone pain or some other clear symptom of metastatic disease)
  • The development of more than three sites of metastasis
  • Local progression (growth) of the metastases identified at time of enrollment into the trial

Here are the study findings:

  • 62 patients were enrolled between August 2012 and August 2015.
  • The average (median) follow-up was 3 years
  • The median ADT-free survival times were
    • 13 months for the patients in the surveillance/monitoring group
    • 21 months for the patients in the MTD group
    • Hazard ratio (HR) = 0.60
  • Quality of life  between the two groups of patients was similar
    • At baseline
    • At 3 months of follow-up
    • At 12 months of follow-up
  • 6 patients in the MTD group developed grade 1 toxicity (but no grade 2 to 5 toxicity was observed).

The authors conclude, straightforwardly, that

ADT-free survival was longer with MDT than with surveillance alone for oligorecurrent [prostate cancer], suggesting that MDT should be explored further in phase III trials.

Now we should add that it is important to recognize that a progression-free survival benefit does not always correlate with an overall survival benefit. In other words, being able to delay initiation of ADT does not necessarily imply an increase in overall survival when long-term ADT (continuous or intermittent) is actually initiated. The implication of this is that the ideal Phase III trial in such patients might need to randomize patients as follows:

  • 600 patients to be randomized to initial surveillance/monitoring
  • 600 patients to be randomized to MTD, with
    • 200 patients to be treated by surgery
    • 200 patients to be treated by SBRT alone
    • 200 patients to be treated by SBRT with (say) 4 or 6 months of neoadjuvant ADT, because we know that the combination of ADT + radiation therapy has a synergistic effect

All patients would then need to be followed for both ADT-free survival and time to onset of castration-resistant prostate cancer (because the latter is a reasonable surrogate for overall survival).

So we are talking about a pretty large and long Phase III trial if we are really to know what “the best” way is to treat men with oligometastatic recurrence of prostate cancer that was originally treated with curative intent. Is such a trial doable in the USA today? Hard to know … but probably not unless there is new funding for the national clinical trials initiatives.

15 Responses

  1. I read this study several days ago and had several big problems with it. I wrote to Dr. Ost for clarification and comments, and will give him a few more days to respond. Based on what I read, this should not have been published.

  2. I think this study shows that it is more likely than not that removing metastases is beneficial.

    A further study should use a PSMA PET/CT instead of a choline PET/CT. The patient may be oligometastatic using a choline PET/CT but polymetastatic using a PSMA PET/CT.

  3. The abstract in the link did not provide any additional data than Sitemaster reported in his post. The 13-month median vs. 21-month median combines the less than 3 months and more than 3 months PSADT patients. It would be very important to know how these two groups fared on an independent reporting basis. I would expect the median ADT-free survival time for the faster PSADT patients to be much shorter than the median reported 7-month benefit. Considering the cost, time, risk, and pain involved in, for example, a pelvic lymph node dissection, a patient would want to know in advance how much ADT-free time he might gain (which I believe is a reasonable goal). I submit that PSADT, a surrogate to disease progression, is a crucial factor for the patient to weigh when deciding on whether to proceed with MDT. Frankly, I don’t think the reported 7-month difference is very significant in the long run.

  4. I did hear back from Dr. Ost and have reviewed the full text. What had shocked me was their use of an 80% confidence interval for statistical significance. The authors pre-specified an 80% confidence interval for this pilot study. This is unusual. In fact, I have never seen it used before. Ostensibly, this was because they knew they would be implementing an expanded Phase III study and only wanted to check for gross differences in this Phase II pilot study. In a more conventional statistical analysis, the hypothesis that MDT affected ADT-free survival would have been rejected. Also, at 80% confidence, they should have accepted the hypothesis that the higher number of metastases in the Surveillance group (a fluke attributable to the small sample size) made a difference — but the authors seem to ignore the inconsistency. Because of this, patients and clinicians are cautioned to not make changes in treatment decisions based on this.

    Because “polymetastatic progression” was the endpoint used to determine whether ADT was indicated for treatment, and 39% of the Surveillance group were already starting with three metastases at baseline, it is surprising that it took 13 months for a single new metastasis to become detectable in that group, and that for 19% of the Surveillance group, a fourth metastasis never became detectable throughout the 3 years of follow-up. In the MDT group, four new metastases had to become detectable after the first ones were eradicated by treatment. 31% (11 of 31) had a second round of treatments, and 6% had a third round of treatments before the sudden appearance of four or more detectable metastases all at once. By setting “ADT-free survival” as the endpoint and making it conditional upon the simultaneous detection of four metastases, they guaranteed that the endpoint would be reached earlier in the Surveillance group. What is surprising is that even with that built-in bias, the difference was not significant with 95% confidence. It is also worth noting that in a pre-planned subgroup analysis, there was no significant difference in ADT-free survival (even at 80% confidence) among those who had a PSA doubling time at baseline of < 3 months. Patients with "indolent" metastases did not benefit from MDT. This study does not show that metastatic progression was slowed by MDT. Only an improvement in overall survival time can show that.

    This study used a choline PET (F18, I presume) scan to detect metastases. We recently saw that there is a clinical trial at Johns Hopkins to detect and treat oligometastases using the more accurate PSMA PET scan. While outcomes may be improved with a more accurate scan, it will undoubtedly eliminate many patients from the oligometastatic pool of patients.

    This study did not investigate whether salvage radiation to the entire pelvic lymph node field would have had better outcomes than spot SBRT treatment. We are still not very good at finding cancerous lymph nodes and the treatment field is inadequate most of the time.

    Importantly, this study does not address whether it is beneficial or detrimental to delay start of ADT. The 8-month delay in the start of ADT may result in 8 months that the cancer is systemically multiplying and evolving. The TOAD trial suggested that early amelioration of the micrometastatic burden in recurrent patients may have a greater influence on survival than any selective evolutionary pressure that starting earlier may exert. It furthermore showed that overall quality of life was unaffected by the earlier ADT start. ADT is the standard of care when metastases have been discovered. Clinical trials of oligometastatic MDT should include ADT use in both arms to give a realistic appraisal and to be ethical.

    While this trial was done among recurrent patients, the STAMPEDE trials, the CHAARTED trial, and the LATITUDE trial among newly-diagnosed patients proved that aggressive systemic therapy, as early as possible after metastases are discovered, provides significant survival advantage.

    It is important that patients understand the very real risk of avoiding systemic treatment when there are known metastases. While it risks little to treat those oligometastases that can be safely treated, we must understand that there is no known survival benefit to doing so. There is a known risk to delaying systemic therapy. Dr. Ost wrote to me, "MDT does not replace ADT and our results should not be interpreted in that way."

  5. Dear Allen:

    I feel obliged to point out that the issue of the time of initiation of ADT and the impact of that timing on overall survival has never been fully resolved. Dr. Johann de Bono raised this question yet again during an extended discussion after the presentation of the data from the LATITUDE and the STAMPEDE trials at ASCO last year.

    The TOAD trial was a better attempt than most, but it still had significant flaws, and there are very real questions about when to start ADT in men with metastasis but a relatively long PSA doubling time (let alone the men with a rising PSA but no signs of metastasis). We need to remember that for a significant subset of men, the side effects of ADT are seriously debilitating.

    I would respectfully submit that — quite apart from the issues of when and how to treat oligometastasis, we also still need to get some truly definitive data about when it is best to initiate ADT in a broad spectrum of very carefully stratified patients.

    Some physicians would disagree with you strongly and say that ADT is not actually the proven standard of care “when metastases have been discovered”. They would state that ADT with either chemotherapy or abiraterone acetate + prednisone (with or without radiation therapy as appropriate) was now the standard of care in men initially diagnosed with metastatic or perhaps even lymph-node positive prostate cancer, but that there is no defined standard of care for men with metastasis as a consequence of progressive prostate cancer for the simple reason that ADT has only ever been proven to be palliative as opposed to offering a survival benefit.

    Of course there are all sorts of possible reasons to quibble about this, but I am in Dr. de Bono’s camp. We seriously need a major trial to establish once and for all whether early initiation of ADT provides a sufficiently significant survival benefit compared to delayed ADT such that all the risks associated with quality of life are far outweighed by the benefits of extended life. The careful stratification of patients in this trial will be critical, but my gust sense is that early ADT only provides a compelling benefit for a subset of men who progress after first-line therapy for intermediate-risk and high-risk disease … and I am not ecven sure that we know how best to define and subcategorize those patients.

  6. There are three situations in which ADT is required with recurrent disease:

    1. Known presence of symptomatic metastases
    2. High PSA
    3. Rapid PSADT

    I really don’t think there is any controversy about that. One can quibble about just how high the PSA ought to be, or how rapid the PSADT must be. One can quibble about which kinds of ADT are best and which other systemics are best to add in addition to ADT. One can quibble about whether ADT ought to be intermittent or continuous. But one can’t quibble about the fact that ADT is the current standard of care when metastases have been discovered, especially if they are symptomatic.

    NCCN (certainly one of the definers of standard of care) writes this in their current physician guidelines: “ADT is the gold standard for men with metastatic prostate cancer.”

    ASCO agrees:

    “1. What Are the Standard Initial Treatment Options?
    Bilateral orchiectomy or medical castration with luteinizing hormone–releasing hormone (LHRH) agonists are the recommended initial treatments for metastatic prostate cancer.”

    All the major recents RCTs (STAMPEDE, CHAARTED and LATITUDE) have proven that in men with detected metastases, early initiation of ADT with various adjuvant therapies, even before symptoms appear, have a significant survival benefit.

    Your contention that ADT is only palliative and has no proven survival benefit is simply untrue. The survival benefit of ADT has been well established since Huggins and Hodges in 1941. More advanced forms of ADT have had to prove survival benefit ever since then. If what you meant to write is that it is not curative for metastatic disease, that is certainly true and no one would argue that.

    Given the body of data, to withhold the known survival benefits of ADT for questionable survival benefits of MDT strikes me as unethical, especially since they can easily both be done.

  7. Dear Allen:

    Something can be a standard of care for historical reasons without ever having proven a survival benefit. Huggins and his colleagues never established a survival benefit. There was never any trial done that was even designed to demonstrate that. They established a pain relief benefit (i.e., a quality of life benefit) associated with treatment with ADT alone in men initially diagnosed with serious, widespread, metastatic prostate cancer and associated bone pain. No one is arguing about that. But that is, by definition, palliative care.

    We also now know that, in patients similar to those treated by Huggins and his colleagues, i.e., men initially diagnosed today with widespread metastatic disease, those patients should receive immediate combination therapy with ADT + docetaxel or ADT + abiraterone acetate (or perhaps all three?), with or without radiation therapy as appropriate, because this provides a survival benefit compared to ADT alone.

    However, …

    The critical issue that people like Dr. de Bono and others are focused on is whether, compared to the immediate onset of a spectrum of side effects, the early use of ADT alone in men with asymptomatic and minimally metastatic prostate cancer has any survival benefit. We have no clear evidence to demonstrate that. Not even from the STAMPEDE and other trials. This is not a matter of “quibbling”. If there is no real survival benefit for such men, and maybe only a minimal progression-free survival benefit, then they are at significant risk for unnecessary over-treatment and for the unnecessary early induction of mCRPC, which is quite certainly a real problem.

    And no, I did not mean to write that ADT is not “curative” for metastatic disease. As far as I am aware, no form of therapy has ever been proven to be “curative” for metastatic disease — although there do certainly appear to have been selected patients with oligometastatic disease who have been placed in long-term and even very long-term remissions by combination of ADT with radiation therapies of differing types.

    I would argue that — based on the available data — it is now quite certainly unethical to initiate ADT alone in men with clear evidence of rapidly or potentially rapidly progressing or symptomatic, metastatic or even micrometastatic prostate cancer … but that it may well be equally unethical to initiate ADT alone in men with asymptomatic, minimally metastatic prostate cancer with a long PSA doubling time.

    The question therefore is, how do we do the right trial to determine whether, in fact, there is any role whatsoever for ADT alone in the treatment of advanced prostate cancer today? It would be impossible to do such a trial without randomizing some men to monitoring … and monitoring of men with asymptomatic, minimally metastatic prostate cancer with a long PSA doubling time is certainly an option, but so is some form of treatment if they have oligometastatic disease — because that may be curative in at least some patients.

    I would also and finally note that when the LHRH agonists were introduced in the 1970s, they did not have to demonstrate a survival benefit compared to any earlier form of ADT. What they had to demonstrate was the same level of palliative care compared to treatment with orchiectomy (i.e., by lowering serum T levels to < 50 ng/dl). They never had to show any survival benefit in the treatment of metastatic prostate cancer to gain approval. The addition of the first antiandrogen (flutamide) to an LHRH agonist (leuprolide) did show a survival benefit of 7 months in one large pivotal trial in 1989, but that result has never been replicated, and that trial was actually initiated to prove that there was no benefit to the addition of an antiandrogen to an LHRH agonist. That result was never expected. The primary benefit of antiandrogen therapy is that it suppresses the LHRH flare reaction at the start of LHRH therapy. Antiandrogen therapy can also re-suppress PSA levels temporarily when added to an LHRH agonist at the earliest stages of onset of CRPC — but this is an extension of the palliative care effect; there is no suggestion of a true survival benefit.

  8. Mike,

    I’m very relieved to hear that you do agree that systemic hormone therapy is the standard of care in men with metastatic prostate cancer, and that it does improve survival, at least in combination of hormonal or systemic agents, as proved beyond a shadow of a doubt by the Phase III efficacy trials of abiraterone and enzalutamide as well as several recent trials. We seem to agree on that much.

    As an aside, I would point out that the 1989 leuprolide + flutamide vs leuprolide + placebo in 603 metastatic patients did find that “Median length of survival for the leuprolide and flutamide group was 35.0 months and 27.9 months for the leuprolide and placebo group. … Patients with minimal disease and ECOG performance status between 0 and 2 demonstrated the most significant differences between treatment groups in terms of progression-free survival and overall survival.” It is always the null hypothesis in every efficacy study ever done that the treatment had no effect. That does not mean that “that result was never expected,” it just means that the null hypothesis has to be rejected with 95% confidence. That is the way all research is done. Early use of hormone therapy in metastatic men is well established, which is why it was picked as the one to beat in CHAARTED, STAMPEDE, and LATITUDE.

    You seem to be on a tangent about when to start hormone therapy, and what is the best systemic therapy to start with. We should be clear that TOAD was different in terms of different patient populations from CHAARTED, LATITUDE, and STAMPEDE (mostly). TOAD primarily looked at PSA-recurrent men before metastases were detected. The other studies looked at newly-diagnosed men who already had detectable metastases (STAMPEDE included a small sample of recurrent and M0 men). The present study only looked at PSA-recurrent men after metastases had been discovered, so this study is starting at a stage beyond what the TOAD study addressed, and probably beyond many of the men in those other studies. If all of those studies proved a survival benefit to early systemic therapy, whether multi-hormonal or hormonal plus chemo, how can a patient ethically be denied systemic therapy while waiting for an experiment on MDT alone?

    The CORE trial in the UK is taking a better, more ethical, approach. Patients are randomized to standard of care (which will include hormone therapy or other systemic therapies at the physician’s choice) or standard of care plus SBRT to detected metastases.

  9. Dear Allen:

    It is the potentially excessive use of ADT alone in men with asymptomatic, non-metastasic and minimally metastatic disease that is of the greatest concern to me. … Its use (in combination with other forms of therapy) in men with clearly metastatic disease or in high-risk men with (probably) micrometastatic disease is a whole different issue.

    And please understand that I am not suggesting (and never have suggested) that anyone should be denied treatment with ADT. All that I am saying is that the customary use of standard forms of ADT alone in men with asymptomatic, non-metastatic and minimally metastatic disease has never been shown to provide a survival benefit. If it isn’t being use to palliate symptoms (because there aren’t any) and we don’t know that it provides a survival benefit, how can that be “ethical” use of ADT alone? We know it can come with devastating side effects and complications for many men. The primary reason for early use of this form of therapy in men with a rising PSA but otherwise asymptomatic, non-metastasic disease was, frankly, financial. It made enormous amounts of money for TAP Pharmaceuticals as well as for the physicians administering the leuprolide.

    Also, I think you may be missing important historical background with regard to the leuprolide + flutamide study from the 1980s. That study was actually done by SWOG because the investigators were all fed up by the unsubstantiated claims being made for the benefits of what was then known as “maximal androgen deprivation” using flutamide + leuprolide coming out of the practice of Dr. Fernand Labrie in Canada. Labrie owned the patient on flutamide in the treatment of prostate cancer in combination with orchiectomy or an LHRH agonist, but his data came entirely from open-label studies. SWOG set out to do this trial with a very clear belief that there would be no survival benefit seen in the study. Schering-Plough was optimistic that there might be a benefit. Frankly, everyone (except Labrie) was astonished by the study results. I was intimately involved in all of this. Even the lead developer of flutamide at Schering was astonished. He had hoped there might be a very small survival benefit. So when I say that the 7-month survival benefit was “unexpected”, that is exactly what I mean. It has nothing to do with the statistics. And, as I have pointed out before, no one has ever been able to repeat this result in another trial of “maximal androgen deprivation” vs. an LHRH agonist or orchiectomy + a placebo instead of the antiandrogen. That’s why long-term maximal androgen deprivation isn’t the standard of care (as compared to short-term use of an antiandrogen to prevent the flare reaction associated with initial injection of an LHRH agonist).

    The CORE trial is an excellently designed trial, but it still isn’t addressing the problem that both Dr. de Bono and I have raised on more than one occasion. I an sure you appreciate that Dr. de Bono is probably one of most knowledgeable specialists in the treatment of advanced prostate cancer (and the conduct of trials in the treatment of advanced prostate cancer) working anywhere in the world today. Neither he nor I would concur that we are “on a tangent” regarding when to start hormone therapy. The issue for both of us is when and how to initiate appropriate treatment in men with asymptomatic, non-metastasic and minimally metastatic disease. The CORE trial is really a trial of SBRT in treatment of minimally metastatic disease. It is not a trial of whether ADT is being appropriately used in men with a rising PSA, no symptoms, and no clear evidence of metastasis.

  10. The NCCN guidelines (PROS-8/9) specify observation as a valid option in a recurrent situation. This is defined in the guidelines as: “Observation involves monitoring the course of disease with the expectation to begin ADT when symptoms develop …” So it is not unethical to observe the patients in the control arm instead of treating them with ADT. If you add ADT to a trial you need a much longer time to observe the included patients to get results. Therefore this trial was designed without ADT.

    I do not think we can gain valid information from the TOAD study and the timing of ADT remains unclear. Fakhrejahani et al. comment on the TOAD study as follows:

    “One noteworthy limitation of the study was that some patients with metastatic disease were enrolled on the trial and were included in the final OS analysis which showed a statistical difference between two groups. These findings are misleading and do not inform the management of BCRPC (biochemical recurrent prostate cancer). When the metastatic patients are excluded from the analysis, leaving only the BCRPC patients, there was no statistical difference in OS between the two groups of patients. [!!] The other limitation of this study was that patients were mostly recruited from centers that were specialized in radiation treatment thereby limiting enrollment of patients who had surgery as their primary intervention.”

    So I think delaying ADT is a valid option. Instead of ADT the patients can have their metastases removed and lower their PSA values this way. The study by Prof. Ost reports that 75% of the treated patients observed a reduction in PSA value following the treatment. This while treatment was limited to the metastases which were visible with a choline PET/CT instead of a PSMA PET/CT.

    I also want to point out that of the 208 patients asked to participate in the trial, 69 (33%) declined to participate. As Prof. Ost mentioned at a conference, the majority of these refused to be randomized, they insisted to have their metastases treated with SBRT!

    These patients decided without waiting for study results: I do not like to have these metastases in my body! This simply cannot improve my prognosis. So after 69 patients refused to participate, 62 were left to be randomized.

    If you decide against metastasis-directed therapy and choose systemic therapy instead: what will be the resulting course of the disease? As Katzenwadel and Wolf state in their article entitled “Androgen deprivation of prostate cancer: leading to a therapeutic dead end“:

    “… virtually all patients show disease progression at a median of 18–24 months after the beginning of treatment despite maintenance of castrate testosterone serum levels …” and later “… it seems to be time for a fundamental paradigm shift in the treatment of advanced PCa. Therapeutic intervention seems to be indicated for higher efficacy before a castration-resistant stage is reached.”

    Metastasis-directed therapy could be such a therapeutic intervention. If you have to start with ADT sometime after that, you still can add docetaxel or abiraterone.

    George

  11. I would add to George’s reference to the Katzenwadel and Wolf abstract the recent commentary by Dr. Charles Ryan about treatment-mediated selection pressure.

    As Dr. Ryan states: “Early ADT — by stressing the tumor -– may give remaining malignant cells time to adapt, mutate, and amplify their way to treatment resistance and lethality. ”

    The main potential benefit of MDT is to treat metastasis without ADT, thereby preserving hormone-naive status and theoretically delaying mutation of the cancer into a castration-resistant state. Given the real possibility of accelerated castration resistance of early ADT, I fail to see how recommending delayed ADT is unethical. Nevertheless, I enjoyed and learned from the point/counterpoint discussion by Sitemaster and Allen. Thank you!

    Richard

  12. (I posted this yesterday, but it got lost somewhere in Internetland. Please trash if it’s a duplicate)

    Mike:

    You are on a tangent here because the subject of your commentary was MDT in metastatic patients. I think you are commenting on whether ADT is effective at all. One has only to look at prostate cancer survival before and after hormone therapy to know it does. Survival has increased steadily since that discovery. We don’t have to go back to square one — no one would ever do an RCT where metastatic men were randomized to be deprived of ADT (at least I hope not).

    But if you want to discuss the use of antiandrogens…

    I am pleased to learn that you were all surprised by the outcome of the flutamide + leuprolide trial. That is as it should be — a good RCT should disprove skeptics. I have yet to hear what was wrong with the trial. It is incorrect that “no one has ever been able to repeat this result in another trial of “maximal androgen deprivation” vs. an LHRH agonist or orchiectomy + a placebo instead of the antiandrogen. That’s why long-term maximal androgen deprivation isn’t the standard of care (as compared to short-term use of an antiandrogen to prevent the flare reaction associated with initial injection of an LHRH agonist).” Boccardo and Eisenberger found no significant difference in benefit with the addition of an antiandrogen, whereas Dijkman proved there was a 7-month improvement in PC-specific survival with the use of nilutamide. A meta-analysis in 2000 showed that 5-yr survival increased from 24.7% to 27.6% with the adjuvant use of those early anti-androgens, which was statistically significant, if not particularly meaningful.

    In 2009, Akaza reported that the combination improved overall survival from 63.4% in the LHRH-A monotherapy group to 75.3% in the combined androgen blockade (CAB) group. Like the 1990 Crawford RCT, the authors reported in subgroup analysis that CAB had the greatest effect in those with early stage disease. In fact, they found no effect in late stage disease. While these were planned subgroup analyses, they do suggest a benefit to hormone therapy, and perhaps enhanced hormone therapy, in the treatment of early metastatic disease.

    More powerful antiandrogens undoubtedly do even better in increasing survival. Enzalutamide + LHRH agonist, has certainly proved a survival advantage over LHRH agonist alone. Clinical trials of apalutamide + LHRH agonist and darolutamide + LHRH agonist will hopefully prove beneficial as well.

    While I agree that anti-androgens are given to prevent testosterone flare, it is not true that there is no survival benefit to the enhanced hormonal treatment. Each patient and clinician must decide whether the potential benefit is worth the potential additional toxicity.

  13. Dear Allen:

    I don’t think we are achieving anything here.

    I am not on a tangent, because the question of when and in whom it is appropriate to start ADT affects the appropriate design and structure of any trial being done to test the validity of MDT.

    The issue of second-generation antiandrogens like enzalutamide and apalutamide is an entirely different issue because they have radically different MOAs to the first-generation agents.

    Also, as two others have now pointed out (and the NCCN concurs with) … it is entirely ethical not to give a patient with metastatic disease ADT alone if they are asymptomatic and the patient agrees. It would be unethical only if the patient was not advised about the pros and cons of early vs. delayed ADT in his particular case.

    You are welcome to your own opinions about all this, but your opinions appear (to me) to be biased by some erroneous interpretations of the available data. In particular, I was delighted to see Dr. Ryan’s comments recently (just noted by Richard Staunton) that early use of ADT did indeed increase the potential risk for early onset of CRPC … something that I have been pointing out for years. That’s a biological inevitability.

  14. Richard:

    We have to separate conjectures (which are wonderful for testing hypotheses) from real evidence from clinical studies. That Dr Ryan made a comment does not constitute evidence in anyone’s estimation. Neither is the Katzenwald review that George cited a clinical study. While ADT does increase the selective pressure for castration resistance, that is only part of the overall survival story. The competing issue is the reduction in the systemic micrometastatic load by using ADT. The question is — which effect wins? To answer that question, the TOAD study compared survival in men who had failed curative therapies and were not yet detectably metastatic. What they found overturned my previous bias (I had believed, like you, that there was no risk to a delayed start of ADT).

    Dr. Duquesne wrote:

    “The results delivered by this trial have been both unexpected and thought-provoking. Despite the fact that the trial recruitment was prolonged and fell well short of its target, the results are clinically and statistically in favour of immediate intervention when survival and disease progression end points are considered, with hazard ratios around the 0.5 mark … ”

    “The results also add further weight to the hypothesis that treating small volume or occult disease is more effective than treating overt disease …”

    “One of the most thought-provoking findings was that the development of the castration-resistant phase occurred significantly earlier in the men who started treatment after a delay, a counter-intuitive finding. This may again be linked to treating low volume disease before it grows resistant clones.”

    Moreover, a recent update with more data showed that there was no detriment to an early start on overall health-related quality of life.

    Importantly, that study did not address hormone therapy in men who were already detectably metastatic (which is the issue for MDT), but it does show that reducing the micrometastatic burden with hormone therapy trumps the selective pressure of a later start (as Dr Ryan conjectured).

    Mike:

    The issue is whether it is ethical not to use hormone therapy in a clinical trial of men who are already detectably metastatic. If you want to make that hormone therapy abiraterone + Lupron, I would be very happy indeed that my ethical reservations are adequately dealt with. STAMPEDE and LATITUDE proved that early start of that hormone therapy, as soon as metastases were detectable, extended survival, so how can we ethically withhold it in a clinical trial?

    I don’t really see why you cling to your outmoded opinions that hormone therapy (in various incarnations) does not prolong survival in light of all the studies I cited to the contrary. I can only guess that it’s a result of confirmation bias.

    I am certainly glad the CORE RCT will include hormone therapy in both groups.

  15. Dear Allen:

    In no statement that have I ever made have I ever even suggested that “hormone therapy (in various incarnations) does not prolong survival”. You keep mis-hearing what I am saying. There are forms of androgen deprivation therapy that most certainly do prolong survival, but they do not include “standard ADT” alone. The most impressive of these trials, for me, was the most recent STAMPEDE data using standard ADT + abiraterone + prednisone or prednisolone (ADT+AP), with or without radiation therapy as appropriate, in men with N1M0 and NxM1 disease. Of course the cost is a huge problem, but that will go away relatively soon, once abiraterone is generically available, and there is a very real problem with the use of long-term prednisone or prednisolone. In these patients the question now is whether intermittent ADT+AP might be as effective as continuous ADT+AP and may come with a higher quality of life.

    Let me say this yet again … My problem is exclusively with the continuing use of standard ADT (i.e., an LHRH agonist or an orchiectomy, with or without long-term antiandrogen therapy) alone in the presence or the absence of metastases, and especially in those men with less aggressive forms of progressive prostate cancer who have a slowly rising PSA.

    And with regard to the TOAD trial, I have discussed this directly with Dr. Duchenne. I am in complete agreement with the statement that, “The results also add further weight to the hypothesis that treating small volume or occult disease is more effective than treating overt disease ….” In fact, what that trial does is confirm my opinion that a much larger trial, without all the flaws that appeared in the TOAD trial, is still needed. It should be limited to men with non-metastatic disease (and perhaps even to men who are PSMA PET/CT scan negative for signs of disease in their lymph nodes or beyond) and it should be stratified by prior treatment type, by PSA doubling time (e.g., less than 6 months, 6 to 12 months, and more than 12 months), and probably by original clinical risk (low or favorable intermediate risk vs. unfavorable intermediate or high risk).

    I also have no problem with the CORE trial … but if you aren’t going to actually treat a man using SBRT for oligometastatic disease (in which case I agree that adding short-term ADT or perhaps better yet, short-term ADT + abiraterone, is almost certainly a good idea), then I am unconvinced that anyone should be getting true, standard ADT alone.

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