Timing of initiation of ADT for men with biochemical progression after first-line surgery

For many years your sitemaster has been advising patients that overly early use of androgen deprivation therapy (ADT) in many men with progressive prostate cancer is not necessarily the best decision (for a number of possible reasons). The benefits of such early ADT — in terms of metastasis-free survival (MFS) and/or overall survival (OS) — have never been categorically proven to outweigh the risks of the well-understood side effects.

A newly published paper by Marshall et al. — from Johns Hopkins (in Baltimore, MD) and the Center for Prostate Disease Research at the Uniformed Services University of Health Sciences (in Washington, DC) has now provided additional data supporting this premise for definable subsets of patients with a rising PSA after initial treatment.

What Marshall and her colleagues did was to conduct a retrospective analysis of prospectively collected data from 806 patients initially diagnosed with localized prostate cancer and treated with first-line surgery (a radical prostatectomy) at either Johns Hopkins or at Walter Read National Military Medical Center between 1983 and 2014. All 806 of these patients met the following additional criteria:

  • They developed biochemically recurrent prostate cancer post-surgery with a PSA doubling time of < 10 months.
  • They could also have been treated with salvage radiotherapy alone (but not salvage radiotherapy together with ADT).
  • They received no other prostate cancer-specific treatment until they showed clear evidence of metastatic disease.

The following information is also relevant:

  • Average (median) age of the patients was 61 years at time of initial surgery.
  • Of the 806 patients
    • 132 (16 percent) were African American
    • 639 (79 percent) were Caucasian
    • 35 (5 percent) were of other or of unknown ethnicity
  • Pathological (post-surgical) Gleason scores for 746 of the 806 patients were
    • Gleason 6 or less in 124/746 (17 percent)
    • Gleason 7 in 403/746 (54 percent)
    • Gleason 8, 9 or 10 in 219/746 (29 percent)
  • Pathological T stages for 786 of the 806 patients were
    • T2 for 247/786 (31 percent)
    • T3/4 for 539/786 (66 percent)
  • Positive surgical margins were evident among 304/799 (38 percent) of the 806 patients.
  • Negative surgical margins were observed among 495/799 (62 percent) of the 806 patients.
  • 304/ 806 patients (38 percent) had died by the time of data analysis (which is assumed to have been in about 2018 or 2019, but this is not explicitly stated in the paper)
  • At time of initial onset of metastatic disease, all patients received initial systemic treatment with ADT alone.

Based on these data, Marshall et al. were able to make the following determinations:

  • Average (median) time to onset of metastatic disease from time of initial surgery (metastasis-free survival or MFS) was
    • 192 months (16 years) in men with a PSA doubling time of < 10 months
    • 144 months (12 years) in men with a PSA doubling time of < 6 months
  • Average (median) overall survival (OS) from time of surgery was
    • 204 months (17 years) in men with a PSA doubling time of < 10 months
    • 166 months (nearly 14 years) in men with a PSA doubling time of < 6 months

In other words, a man of 65 years of age initially treated by radical prostatectomy who had a biochemical recurrence post-surgery with a PSA doubling time of < 10 months would — on average — reach 81 years of age before showing any sign of metastasis.

Other findings included the following:

  • African America patients were significantly less likely to exhibit metastatic disease than Caucasian patients (hazard ratio [HR] = 0.5).
  • Time from initial surgery to biochemical recurrence correlated with risk for metastatic disease (HR = 0.5).
  • A PSA doubling time of < 6 months was significantly associated with greater risk for development of metastatic disease than a PSA doubling time of < 10 months (HR =3.2).

We would point out the following additional facts:

  • All of the patients in this cohort can be classified as high risk for one or more reasons.
  • All of the patients in this cohort were treated exclusively with systemic ADT as their first-line therapy once there was evidence of metastatic disease.
  • Assessment of evidence of metastatic disease in this patient cohort was limited to data from bonce scans and CT scans.
  • Few of these patients are likely to have received drugs like abiraterone acetate or enzalutamide after progressing on ADT, which may well have affected their overall survival.

Marshall et al. conclude as follows:

Men with biochemically recurrent prostate cancer, who defer hormone therapy until metastasis have overall survival that is quite long and the early initiation of continuous androgen deprivation for biochemical relapse, may not meaningfully improve overall survival.

An associated editorial commentary on this article (by David VanderWeele, MD, and Maha Hussain, MD) come to very similar conclusions.

Now we should be clear that there certainly are some patients who should not be advised to defer ADT until time of metastasis (probably including those with a PSA doubling time of < 3 months at time of recurrence). On the other hand, it is becoming increasingly evident that many men may be well advised to defer initiation of ADT for a considerable period of time if this seems reasonable, given the well-established side effects of ADT. The problem is that we still don’t really know what is the “best” scenario for each definable subset of men who progress after first-line treatment for localized and locally advanced, clinically significant prostate cancer. Future data and the continuing evolution of “precision medicine” may be able to assist us in this arena.

Editorial note: We would like to thank Catherine Handy Marshall, MD, for promptly providing us with a full-text copy of this article.

9 Responses

  1. Sitemaster,

    I agree completely with the idea that when possible (which would be in most cases), deferral of commencement of ADT is a reasonable (non) treatment option in the biochemical recurrence context. As you know, the NCCN Guidelines, Version 2.2021, recognize this as an option (“observation”) for high risk and very high risk patients post RP with PSA persistence. In my opinion, the only thing that early initiation of ADT monotherapy cures is PSA anxiety. For some men, however, that is very important.

    Best regards,


  2. While I didn’t understand much of the article, I certainly appreciate the site master’s diligence and dedication to this subject. Thank you.

  3. Is it a typo and it should be 6 months and not 0.6 ?

    A PSA doubling time of < 0.6 months was significantly associated with greater risk for development of metastatic disease than a PSA doubling time of < 10 months (HR =3.2).

  4. Thank you Sophie. It was a typo and has now been corrected!

  5. Thank you!

  6. Hi All,

    A routine blood test at 47 showed a PSA of 12 ng/ml. Three months later I had a radical prostatectomy. The post-surgical pathology showed Gleason score 3 + 4 – 7; ECE 0.4 mm; a single focus of positive surgical margin (0.1 mm grade 3 at margin); no involvement of seminal vesicles or lymph nodes.

    My PSA wasbundetectable for 4 years, Then one year later (fifth year post-surgery) a PSA test results was 0.01 ng/ml; waited a month and now PSA is 0.02 ng/ml. The PSA seems to have doubled in 1 month or the PSA value of 0.01 ng/ml occurred some time within the year before fifth-year post-surgical test.

    What is the consensus to do next?

    Thanks Ian

  7. Dear Ian:

    I am not aware that there is any “consensus” about what to do in this situation. It is certainly possible that your PSA is rising and that you may need early salvage radiation therapy. However, there are other possibilities at play here as well. Unfortunately, your PSA level is currently too low for you to be able to have even a PSMA type of PET/CT scan and get an accurate result as to the location of any recurrence.

    The bottom line is that you and your urologist need to come to a shared decision as to whether you need to have salvage radiation therapy now or whether you should have at least one more ultrasensitive PSA test before coming to any decisions.

  8. Ian:

    Doubling time is not valid for PSAs under 0.1. Your PSA is too low to call for immediate salvage. Three randomized controlled trials have now proved that there is no need to consider salvage until there are three consecutive increasing PSAs or PSA has reached 0.1 ng/ml. In fact, with your 4 years of undetectable PSA, Gleason score < 8, and no PSA doubling time, you fall into the category of men that can be safely watched:


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