PCa Commentary | Volume 208 – December 2025

Posted by Edward Weber, MD | December 2025

Androgen Deprivation Therapy (ADT) — Continuous or Intermittent: That is the Question. — Or Possibly … No ADT Until Metastases.

Trials and reviews comparing intermittent androgen deprivation (IAD) to continuous androgen deprivation (CAD) have been ongoing for more than twenty years, with the near consensus that the survival outcome of both treatments is equivalent. Many studies have compared the two regimens in hormone-sensitive non-metastatic PC (rising PSA after primary therapy) and in metastatic castration-resistant PC. This Commentary reviewed more than a dozen articles on this topic. Initially, there was hope that IAD would prolong both the development of hormone resistance and overall survival, but neither was achieved. However, in nearly all studies, IAD was found to be “non-inferior” to CAD, but with better preserved sexual function and quality of life.

An important consideration regarding testosterone recovery after Lupron discontinuation:

Many studies have evaluated the timing of T recovery and have made the observation that T recovery lags months after Lupron discontinuation. After a 3-month Lupron treatment, the median time to T recovery is ~ 12 months; after 6 months of treatment, ~ 80% of men recover baseline by 15 months. With IAD, therefore, most of the ”off-time” is spent with subnormal T levels with its attendant adverse effects.

A comprehensive review (Karim, Cancers. 2025) assessed the outcome of early androgen deprivation therapy (ADT) and concluded there was no advantage for treatment before the diagnosis of metastases. Twenty-six studies were reviewed. Predictors of early progression included a short PSA Doubling Time, a high Gleason score, and progression shortly after primary treatment, although these features don’t exclude men from ADT delay, since, although at high risk, progression may be very low.

Studies of IAD vs CAD in men with PSA-only relapse:

1. Salciccia et al., Clinical Genitourinary Cancer. In 2024, compared IAD to CAD in 170 men who were PET/CT and bone scan-negative, experiencing a rising PSA after primary surgery or radiation (i.e., non-metastatic hormone-sensitive PC). At 5-year follow-up, the freedom from progression to non-metastatic castration-resistantPC (CRPC-M0) was 98.8% in the IAD group vs 90.6% for CAD (P=.03), establishing the near similarity of the outcomes of the two regimens.
2. Crook, NEJM. In 2012, studied IAD vs CAD in 1436 men with PSA recurrence after radiation therapy and found the two regimens were equal as to overall survival, but IAD produced better quality of life. Androgen deprivation was initiated at PSA 3 ng/mL, administered for 8 months, then stopped and restarted at PSA 10 ng/mL.
3. Garcia-Albéniz (European Journal of Cancer, 2015) “Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse” reported similar survival in those men undergoing immediate ADT after [PSA] relapse to those who delayed treatment until progression on any imaging technique, development of severe cancer-related symptoms, or acquiring a PSA DT of <6 months.

Studies of IAD vs CAD in metastatic disease:

1. Calais da Silva, Eur Urol. In 2009, researchers found equal survival in men with advanced or metastatic PC treated with IAD or CAD. For men on IAD, 52% of the time was spent off treatment.
2. Sciarra, Eur Urol. In 2013, reported 7 phase 3 trials treating men with metastatic cancer that found no difference in overall survival between IAD and CAD. In their review, “patients spent most of their time on, rather than off ADT.” “The QOL benefit of IAD appears to be modest at best. With IAD, QOL is likely influenced by the duration of the off-treatment periods and the rate of testosterone recovery.”
3. Maha Hussain, ASCO 2012 Annual Meeting: reported on 3040 men with hormone-sensitive metastatic PC with extensive disease. ADT + Casodex were administered for 7 months, and men achieving a PSA of <4 ng/mL were then randomized between IAD and CAD. Those on IAD then stopped therapy, and when their PSAs increased to 20 ng/mL, therapy was restarted and was continued until the PSA was <0.4 ng/mL. This was continued cyclically. If the PSA remained above 0.4 ng/mL after 6 -7 months of treatment switched to CAD.Hussain’s Conclusion:  Overall survival was similar for IAD and CAD for those with extensive metastatic disease; IAD was slightly inferior for those with minimal disease (P=0.08). Median overall survival for men on IAD was 5.1 years vs 5.8 years for CAD.

[For clarity, note that Hussain studied men with CRPC with metastases as compared to Marshall (see below) reporting long survivals in men with non-metastatic PSA-only relapse.]

In his editorial in the Eur Urol, 2013, Lawrence Klotz, referring to IAD, states: “Few treatment approaches offer improved QOL, reduced comorbidity, decreased cost, and no adverse survival effect.”

Early or Delayed ADT at Metastases for men with PSA-only relapse after primary treatment?

What is the benefit/harm ratio for ADT (IAD or CAD) when initiated early in asymptomatic men who are non-metastatic and experiencing PSA-only relapse? Can ADT be safely postponed until the diagnosis of metastases on PET imaging or significant clinical symptoms?

The benefit/harm issue between early ADT and treatment delayed until metastases was addressed in a J Urol article in 2022, by Marshall et al., “Timing of Androgen Deprivation Treatment for Men with Biochemical Recurrent Prostate Cancer…”  The study involved 806 men who relapsed following primary surgery for localized disease and had developed PSA Doubling Times faster than 10 months, at which time ADT was initiated. Gleason Score was 7 in 54% and 8-10 in 29%. The study recorded median metastasis-free (mMFS) and median overall survival (mOS) measured from the time of diagnosis. At a median of 9 years follow-up, in those men who entered the study with PSADT <6 months, the mMFS and mOS were 144 and 169 months (14 years); in all men with PSADT <10 months at study start, the mMFS was >192 months, and mOS was 204 months (17 years).

Marshall’s conclusion: “Men with biochemically recurrent prostate cancer who defer hormone therapy until metastases have overall survivals that are quite long, and early initiation of continuous androgen deprivation therapy [or intermittent ADT] for biochemical relapse may not meaningfully improve overall survival.”

Oliver Sartor, MD, Director of the Transformation Prostate Cancer Research Center, Tulane University, offered an editorial opinion in the NEJM, 2012, “Androgen Deprivation — Continuous, Intermittent or None at All?” He raised the key question: “Does early androgen deprivation in asymptomatic men with rising PSA levels provide more benefit than [delaying] treatment in symptomatic men with metastasis?” His opinion was clearly that it doesn’t. And along with his question, he listed all the known adverse effects of suppressed testosterone.

BOTTOM LINE:

Delaying ADT therapy until detection of metastases is at variance with the long-time custom of the earlier application of ADT in PSA-only relapses. However, the weight of evidence reviewed in this Commentary supports the delay option. In the treatment of metastatic disease, this review finds similar survival outcomes for IAD to CAD.

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