Following primary therapy with surgery or radiation in men with high-intermediate-risk and high-risk prostate cancer at diagnosis, the disease will recur in 20 – 30%. The recurrences may involve a small number of metastatic lesions, <5 sites or a few more. When these lesions are within the pelvis, abdomen or bone, this condition is termed oligorecurrent metastatic prostate cancer. An emerging treatment option is metastasis directed therapy (MDT). MDT involves treatment of these lesions with spot radiation such as with CyberKnife radiation. MDT achieves local control in >90% of instances. If oligometastases are found at initial diagnosis, then radiation to the prostate is added to the spot radiation.
Currently there is no consensus whether MDT should be accompanied by androgen deprivation therapy (ADT) or whether androgen suppression is best delayed, thus avoiding the adverse effects of testosterone deficiency. Two major studies evaluated the benefit of combining MDT with androgen suppression in oligo-metastatic prostate cancer.
Combining Androgen Suppression with Stereotactic Body Radiation Therapy (SBRT) in Oligometastatic Prostate Cancer:
The EXTEND Trial: This trial (JAMA Oncol. 2023. Tang et al.) established that the combination of MDT and androgen suppression in men with oligometastatic cancer with 5 or fewer metastatic lesions significantly prolonged progression-free survival (PFS) in comparison to ADT only.
Updated Results of EXTEND as of 2025 found that progression-free survival (PFS) for the combination was 47 months vs 22 months for SBRT alone. MDT+ADT prolonged time to the development of castration resistance. Data on overall survival is not mature, and the early analysis suggests there may not be much difference between the two arms.
The RADIOSA Trial: Marvaso (Lancet Oncol. 2025) also addressed the benefit of adding hormone suppression by comparing 6 months of ADT combined with SBRT to SBRT alone in men with PET diagnosed oligo-recurrent hormone-sensitive prostate cancer with 3 or fewer lesions.
Updated Results showed progression-free survival for SBRT+ADT was 32 months compared to SBRT alone, ~15 months. No overall survival data has been reported and the ”crossover” feature of the trial will likely make it ambiguous.
The authors of the trial considered their results confirmed the benefit of adding MDT to ADT in the oligometastatic setting in regard to progression-free survival. In their opinion the next step was to identify biomarkers to predict response to treatment with SBRT alone thus deferring ADT in selected men to avoid ADT’s well-recognized adverse effects.
The ultimate benefit of adding ADT will differ among men because of the heterogeneity of the condition. The important question is how to identify men in whom ADT may be safely deferred.
DECIPHER: Its Role in Guiding the Decision to Add or Not Add ADT to SBRT:
In men who are metastatic at diagnosis the aggressiveness of the disease can be estimated using the genomic analyzer Decipher. Decipher offers a genomic risk score predicting the risk of clinical outcome, i.e., the risk of cancer specific mortality in 10 yrs. With this estimate of risk, a man can be guided as to whether he wishes to be treated with ADT. In the oligometastatic setting where MDT is being considered, a biopsy of a metastatic lymph node can be submitted to Decipher to assess the aggressiveness of the disease to guide the decision to add ADT.
STRATEGIES to AVOID ADT:
Najdawi et al. addressed this in “Testosterone-Sparing Strategies for Biochemically Recurrent Prostate Cancer After Radical Prostatectomy,” (Current Oncology Reports. 2026). Najdawi was concerned with overuse of ADT in low- and intermediate-risk biochemical recurrences, as defined by NCCN Guidelines Version 4.2024 (essentially specifying Gleason Grade 1 and GG 2 with a low percentage of pattern 4; and PSA up to 20 ng/mL).
The authors presented options for treatment without ADT:
1) Participation in the regimen of active surveillance as opposed to initiating treatment with ADT.
2) Utilization of MDT treating patients selected based on a PET/CT to detect and treat the early evidence of metastatic disease.
3) Adjuvant radiation therapy without ADT. Adjuvant radiation improves PFS and Overall Survival in patients with high-risk characteristics. Men with intermediate-stage disease (Gleason Grade 2 or 3) are heterogeneous as to the benefit of adding ADT to radiotherapy. The decision to add ADT to adjuvant radiation in this group can be guided by utilizing ARTERA AI’s “The Prostate Test,’’ an AI-enabled molecular-pathology tool that supports clinical decision-making regarding the benefit of adding ADT to radiation and the duration of ADT (Available online at ”The Prostate Test).”
4) Enzalutamide Monotherapy for patients with non-metastatic high-risk biochemical recurrence. Enzalutamide alone (unaccompanied by ADT) maintains testosterone levels, produces fewer hot flashes and preserves bone mineral density. Enzalutamide monotherapy could be used as an alternative to Lupron.
5) Radioligand therapy (Pluvicto) alone and in combination with other agents is moving into earlier use in castration resistant prostate cancer without accompanying ADT.
BOTTOM LINE:
The management of prostate cancer is changing – moving away from the customary reliance on hormone suppression (ADT) at metastatic recurrence. New treatment strategies seek to avoid the adverse effects of testosterone suppression in biochemically recurrent disease.