A major, and poorly defined, issue for both patients and clinicians regards the optimal start point for ADT when the PSA is rising after primary therapy with curative intent. Surprisingly, there have only been two major studies that attempt to answer this important question — and they offer opposite conclusions!

Perspective offered by studies on the natural history of prostate cancer after biochemical recurrence:

It is instructive to put the broad issue of the natural history of prostate cancer after a rising PSA into perspective. This insight has been offered by Antonarakis, Eisenberg, Walsh, Partin et al. in BJU Int. 2012 Jan, “The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up”, wherein they give further follow-up and analysis of the original patients in Walsh’s 1999 JAMA article. The purpose of their study was to provide better risk assessment models to identify men who might benefit from earlier additional treatment.

In their study no treatment was given to most patients after PSA recurrence until metastases developed, except for 14% who did receive androgen suppression prior to metastases. The median time to biochemical recurrence for the entire cohort was 3 years and the median metastases-free survival (MFS) was 10 years, “most strongly influenced by PSA doubling time and Gleason score.” The unique protracted natural history of prostate cancer is underscored by the study’s observation that the “Median survival has not been reached after 16 years of follow-up after biochemical recurrence.”

The median initial PSA for the 450 man study group was 8.5 ng/mL. The pathological Gleason scores were 6 (19.9%), 7 (53.1%), and 8-10 (27.3%).”Most patients had pathological non-confined disease and Gleason scores >7,” indicating a greater than average degree of aggressiveness.

The key finding of the study was that:

  • The risk of developing metastases from prostate cancer was strongly related to Gleason score (<7 vs 8-10) and prostate cancer specific antigen doubling time (PSADT).

The 5-year median metastases-free survival (MFS) was stratified according to PSA doubling times:  <3.0 months, 3 – 9 months, 9 – 15 months, and >15 months. The results varied markedly according the PSADT and Gleason score.

Table 3 in the article presents median metastases-free survival in years according to PSA doubling time and pathological Gleason score:

  • For the four categories of PSADTs the median MFS in years is 1, 4, 13, and 15 years, respectively.
  • The MFS stratified for Gleason score: GS 8-10, 4 years; GS 7, 11 years; and for GS 4-6, >15 years.

[Although it has been difficult to establish a benefit for ADT in prolonging overall survival, ADT can clearly postpone the onset of metastases and their attendant symptoms.]

Authors’ conclusion: “Therefore, identifying and treating patients at highest risk of metastases would probably have the greatest impact on patient outcome, especially since most prostate cancer deaths occur in men with metastatic disease.” Although the development of metastases based on PSA doubling time is a continuous variable, a reasonable dividing point for starting ADT based on this data would seem to lie somewhere between a PSADT of 6 to 9 months. For men with higher-risk Gleason scores a PSADT closer to 6 months might be more appropriate for starting ADT.

Two Recent Studies on When to Start ADT.

The question addressed in both these studies is whether there is an advantage to starting ADT “early,” or whether ADT can be delayed as long as possible so as to avoid the toxicity of androgen suppression.  A comparison of the findings in these two articles is presented below. The first of the two studies, based on CaPSURE (a national prospective registry) data, is more statistically solid and likely warrants greater credibility.

Article #1:     “Immediate vs deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. An observational follow-up study,” Garcia-Albeniz, Cooperberg, Carroll et al., Eur J Cancer, 2015 May.

Reports a retrospective analysis of overall survival for 2096 men treated with radical prostatectomy (69%) or radiotherapy (31%). The Gleason score was >7 in 35%. Eligibility required the tumor stage to be <T3a, and lymph nodes and metastases negative. The mean interval for the total cohort from primary therapy to PSA relapse was 37.4 months. [Roughly similar to the figure in the Atonarackis article.]

This study focused on men with low- to moderate-risk prostate cancer — the category most commonly seen. Other studies focusing on higher-risk cancer have shown that earlier ADT intervention is warranted for this much smaller group of men with Gleason score 8-10, early relapse from primary therapy, and the 6% of men with PSA doubling times of < 3 months (Freedland, JAMA, 2005).

In the Garcia study design “We emulated [a randomized trial] by assigning patients to the “immediate” strategy if they initiated ADT within 3 months of PSA relapse and to the “deferred” strategy if they initiated ADT when they presented with metastases, symptoms, or a short [i.e. < 6 months]  PSA doubling time.”  An additional indication for starting ADT was a combination of PSA >10 ng/mL and a PSADT of < 12 months.  ADT could be accomplished with an LHRH inhibitor or orchiectomy.

Study results:  The estimated 5-year overall survival for “immediate “ADT was 85.1% vs 87.2% for “deferred.” The 10-year survival was identical in both groups, 71.6%. There were very few prostate cancer specific deaths.

Study conclusion: “Our study suggests little or no survival benefit for immediate ADT initiation compared with deferred ADT initiation (at clinical progression) among prostate cancer patients with PSA-only relapse.”

The authors cite ASCO guidelines: “The Panel cannot make a strong recommendation for the early use of ADT” … [and] “the critical issue is to determine whether there is benefit and how large it is for starting ADT while patients are asymptomatic.”

Article #2:    The second study: “Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA , [acronym] ”TOAD”: a randomized, multi center, non-blinded phase 3 trial, published in Lancet, June 2016, and was a collaborative effort by 29 oncology centers in New Zealand and Australia.

It had aimed at 750 registrants, but poor accrual led to its early closure, diminishing its statistical power to achieve a firm conclusion. The patient mix was heterogeneous: 261 men were treated at PSA relapse, 32 never had primary therapy and received ADT; some received continuous ADT and others intermittent ADT. For “delayed” ADT the study schema recommended that intervention be delayed for at least 2 years unless clinically contraindicated, i.e. development of symptoms, metastases, or a PSADT of 6 months or less.

At 5 years the immediate treatment group’s overall survival was 91.2% vs 86.4% in the deferred arm.

Terrence Friedlander, MD, prostate cancer specialist, UCSF, who reviewed the study for ASCO 2015, opined “This study is not practice changing, and if there is a benefit to early ADT the benefits are likely to be modest and have to be balanced with the considerable side effects of hormonal treatment.”

What does “Up To Date” Say About This Issue?

“Up To Date” is a subscription-only, highly regarded source of very current evidence-based recommendations for management of most types of cancer. Of interest for this Commentary article is the section written by Judd Moul, MD, Professor of Urologic Surgery, Duke Prostate Cancer Center,  and Mary-Ellen Taplin, MD, medical oncologist, Associate Professor of Medicine, Harvard Medical School: “Rising serum PSA after treatment for localized prostate cancer: Systemic therapy,” updated June 2, 2016. They make some major points:

  1. In the situation the rising PSA after primary therapy, “No adequate data from randomized trials have compared the role of ADT with observation in this setting.”
  1. Regarding “When to initiate ADT-based therapy: The optimal timing …is controversial.”  “Deferral is favored by some, commencing ADT upon the development of metastases or symptoms since there is no consistent evidence for a significant survival benefit with ADT in this setting … .” [ i.e. at the point of a rising PSA.]
  1. They cite the CaPSURE data [reviewed above] in which “there was [by some calculations] a 2 percent difference in overall survival when men were treated within three months after detection of PSA increase,” as compared to delayed ADT.
  2. Regarding the TOAD trial [reviewed above]: “ … the trial has too few events to date and will be underpowered to make any definitive conclusions.”
  1. Their suggestions:  For young men at high risk for metastases, i.e., Gleason 8-10 or PSADT of <6 months, they prefer early rather than delayed ADT. “For men with favorable features, such as PSA doubling time >12 months, initiation of ADT can be delayed, with careful informed consent and periodic imaging to assess for metastases.”
  1. What is “early” ADT?  “There is no consensus on what is “early” initiation of ADT, but a practical target is PSA <5.”

BOTTOM LINE When to start ADT if the PSA rises? There are no clear guideline. But there is information and perspective upon which to have an informed discussion with a patient. The PSA doubling time and the Gleason score are the best predictors for the onset of metastases and best inform the decision to begin ADT.

[As an assist for calculating the PSA doubling time here is a link. For accurate results the most recent 3 values, preferable more, should be entered. Also note, that in the high sensitivity PSA range of < .2 ng/ml, a rapid PSADT doubling time may not accurately predict the same rapid rate at higher PSA levels.

The link: https://www.mskcc.org/nomograms/prostate/psa-doubling-time [Memorial Sloan Kettering Cancer Center].