PCa Commentary | Volume 197 – January 2025

Posted by Edward Weber | January 2025

ANDROGEN DEPRIVATION THERAPY (ADT)— When —early or delayed, —and how.

After primary therapy about 30% of men who are at high risk for recurrence experience disease progression — indicated by a PSA rising above their post-treatment baseline value. These are men whose initial PSA was above ~20 ng/mL with Gleason scores of 4+3 or higher and a PSA doubling time of < 9 months. This state of rising PSAs applies to two groups of men: those with rising PSAs before androgen deprivation therapy, termed non-metastatic hormone-sensitive PC (nmHSPC), and a second state termed non-metastatic castration-resistant PC (nmCRPC)., i.e., a rising PSA despite a castration level testosterone. The second category is a transient condition since as many as 80% of these men (based on the EMBARK trial) harbor low-burden metastatic disease found on PSMA scanning, despite having been negative on standard CT, bone scans, and MRIs. Clinical management of these two conditions has been heavily researched without a consensus regarding management. This Commentary will discuss the first state, i.e., nmHSPC, which, upon intervention, can result in both benefits – by delaying metastases, and harm — because of a man experiencing adverse effects due to sustained androgen deprivation. Achieving an acceptable balance between the two is the compromise to be determined by a patient and his physician.

Non-metastatic Hormone Sensitive Cancer – A discussion of the timing of Intervention — early in PSA progression or delayed,  i.e., postponing treatment until metastases are diagnosed:

For Perspective:

Marshall et al. (J Urol. Sept. 2021) studied the duration of the development of metastatic disease and subsequent overall survival in men post-prostatectomy who received no ADT until metastases were diagnosed – on CT, bone scan and MRI (not on the more sensitive PSMA PET/CT). The men had clinically localized cancer, 54% with Gleason Score 7 and 29.5% with Gleason Score 8 – 10 who were experiencing rising PSAs. Surprisingly, as measured from the surgery date, the median time to metastases for men with PSA doubling time (PSADT) < 6 months was 12 years and the median overall survival was 14 years. For those men with PSADT of <10 months metastases developed at a median of 16 years with a median overall survival of 17 years.

For comparison, Marshall’s article presented median metastases-free survival (MFS) and overall survival (OS) in comparable contemporary trials (SPARTAN and ARAMIS) of nmHSPC employing therapies combining Lupron with an androgen receptor inhibitor (apalutamide or darolutamide). In the apalutamide study (SPARTAN), as in Marshall, the men also had PSADTs of <10 months: OS, 14 years; MFS, 11.3 years. Marshall commented: “Our results align with the estimated OS in the SPARTAN and ARAMIS trials.” Marshall cautioned, however, that they were not offering their data as a suggested standard of care but presented it to provide information for discussion between physician and patient. 

The Marshall study and the two major trials chose to study men with short PSADTs, since men with PSADT’s of >12 months are not considered suitable candidates for intervention.

In an editorial regarding the Marshall trial David VanderWeele and Maha Hussain (experts in the field) commented: “Many patients with prostate cancer (PCa) with biochemical recurrence after definitive therapy receive androgen deprivation therapy (ADT) before developing metastases despite lack of perspective data to support its use … . Until definitive data are available, men with BCR should be counseled regarding the lack of data to support ADT benefit in non-metastatic BCR.”

Intermittent ADT (vs Continuous ADT)  —  an NCCN Recommended Management Option

Following the decision to initiate ADT, possibly because of a worrisome PSA doubling time, the question arises as to when and how to conduct intermittent therapy. This issue has been studied extensively with the conclusion that intermittent therapy is equivalent to continuous therapy as to overall survival, but intermittent ADT offers improved quality of life. (Reviewed by Perera et al, “Intermittent versus continuous androgen deprivation therapy for advanced cancer.” Nature Review Urology, Aug. 2020)

Perera noted that there is no consensus as to how to manage intermittent therapy when applied in non-metastatic hormone-sensitive cancer. Perera reported that the induction period of ADT is between 7 and 12 months intending to achieve a PSA <4 ng/mL, and if <4 is not reached then ADT is continued. Six major trials were reviewed all differing as to when to restart ADT following the “holiday period,” with restarting at PSA values of >10 – >20 ng/mL being common. Agreed upon however, was the importance of monitoring during the “holiday” with PSA measured every three months and imaging performed if the rate of PSA rise is of concern. 

There are no published accounts of oral relugolix, “Orgovix,” in intermittent ADT despite its more rapid lowering of testosterone to <50 ng/dL in 15 days and, upon cessation, regaining baseline T in 56 days (as opposed to recovery following a three month Lupron injection which required 258 days to recover baseline values).

Trials Aiming to Improve MFS and OS in Men with nmHSPC with High-Risk Features of PSADTs  <6 and <12 months and Gleason Scores  >7  — All Compared ADT Alone:

Two examples: Zytiga/Prednisone +/- Xtandi given for two years significantly improved MFS and OS, for which at 6 years of follow-up the OS was 86% (combo) vs 77% for ADT. The EMBARK trial at 5-yr follow-up found that Zytiga + ADT prolonged MFS by 58%. 

Referring to the work by Marshall, Guenta, reviewing the “landscape” of nmHSPC (Critical Reviews on Oncology, 2024), commented: “Delaying ARSIs [androgen receptor signaling inhibitors] for use at the time of metastatic onset versus anticipating them at the time of biochemical recurrence has not been investigated yet, so it is impossible to assess, at the moment, the proper role of ARSIs in improving OS … .”

Bottom Line:

Currently, there is no consensus as to when to initiate ADT during a rising PSA following primary therapy or to delay intervention until the diagnosis of metastases, leaving this management decision up to the patient and his physician.

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