Deferral of systemic therapy in patients with oligorecurrent prostate cancer treated with metastasis-directed radiotherapy
Review Article | Biomarkers Sciences

Deferral of systemic therapy in patients with oligorecurrent prostate cancer treated with metastasis-directed radiotherapy

Miguel Muniz1 ORCID logo, Daniel S. Childs1, Jack Andrews2, Ahmed M. Mahmoud3, Sean Park4, Oliver Sartor1, Adam M. Kase5, Irbaz B. Riaz6, Bradley J. Stish4, Aadel A. Chaudhuri4, Pradeep S. Chauhan4, Ryan Phillips4, Fabrice Lucien7#, Jacob J. Orme1# ORCID logo

1Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA; 2Department of Urology, Mayo Clinic, Phoenix, AZ, USA; 3Department of Radiation Oncology, Kansas University Medical Center, Kansas City, KS, USA; 4Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA; 5Department of Medical Oncology, Mayo Clinic, Jacksonville, FL, USA; 6Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, AZ, USA; 7Department of Urology, Mayo Clinic, Rochester, MN, USA

Contributions: (I) Conception and design: M Muniz, F Lucien, JJ Orme; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: M Muniz, F Lucien, JJ Orme; (V) Data analysis and interpretation: M Muniz, F Lucien, JJ Orme; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work as co-senior authors.

Correspondence to: Miguel Muniz, MD. Department of Medical Oncology, Mayo Clinic, 200 1st St NW, Rochester, MN 55905, USA. Email: munizrincon.miguel@mayo.edu.

Abstract: Distant metastasis marks a critical transition in prostate cancer, separating potentially curable from canonically incurable disease. Oligometastatic disease, defined as limited metastases (e.g., less than 3, 5, or 10), can encompass different clinical scenarios, including oligorecurrent disease (characterized by a limited number of metastatic lesions that recur after initial definitive treatment), and has emerged as an intermediate or transitional state. While intensified systemic therapies are increasingly applied to metastatic cases, many patients prefer to delay starting castrating therapies. Metastasis-directed therapy (MDT) is a safe and effective alternative to systemic therapy in a subset of patients with well-defined oligometastatic disease. Recent advances in imaging technologies and emerging treatment paradigms pose clinical challenges for patient risk stratification and optimal treatment selection. Here, we explore two key developments in the field: the influence of advanced imaging on clinical decision-making and the growing role of radiotherapy (RT) in oligometastatic disease management. We explore the landscape of novel biomarkers to estimate micrometastatic disease burden, which eludes imaging, using the concept of “liquid tumor burden” (LTB) measured by blood-based markers like circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and tumor-derived extracellular vesicles (tdEVs). Promising data suggest that LTB assessment may refine patient selection for MDT and systemic treatment. These findings suggest potential for a combined approach of MDT and systemic therapy in oligometastatic prostate cancer (omPC).

Keywords: Oligometastatic prostate cancer (omPC); oligorecurrent prostate cancer; metastasis-directed therapy (MDT); radiotherapy (RT); liquid tumor burden (LTB)

Submitted Oct 24, 2024. Accepted for publication Jun 17, 2025. Published online Jun 24, 2025.

doi: 10.21037/atm-24-187

Introduction

Distant metastasis marks a critical transition in prostate cancer. The disease moves from classically curable to canonically incurable. Treatment approaches shift from localized interventions to systemic therapy. However, oligometastatic disease—usually defined as fewer than 3, 5, or 10 metastases—can be seen as an intermediate stage in the natural history of the disease (1). This disease state can encompass different clinical scenarios, including de novo oligometastatic disease (when the patient has metastatic prostate cancer at diagnosis with no prior treatment for localized disease), oligoprogressive disease (when a patient with metastatic prostate cancer develops progression in a limited number of sites while other metastases remain controlled), and oligorecurrent disease (when the cancer was initially treated, e.g., with surgery or radiation, and later recurs with a few metastatic sites). Our review primarily focuses on the latter, but all of these settings, which fall under the broader umbrella of “oligometastatic prostate cancer (omPC)” represent a clinical gray area.

Oligometastatic uncertainty

The clinical uncertainty of omPC stems largely from two major developments in the field. First, the advent of new and highly sensitive molecular imaging modalities—including choline- and prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET)—are changing the perceived stage of disease. Cases formerly classified as biochemically recurrent (M0) using conventional imaging are now re-classified as metastatic (M1) using advanced molecular imaging techniques. More sensitive imaging often influences clinical decision-making toward aggressive, systemic treatment (2-4). After visualizing distant metastases on advanced imaging, providers may understandably feel compelled to initiate androgen deprivation therapy (ADT) with or without other systemic treatments such as androgen receptor pathway inhibitors (ARPIs) or chemotherapy. These treatments carry significant potential side effects and financial costs.

Second, metastasis-directed therapy (MDT) has become a viable treatment option in oligometastatic disease with the benefit of delaying or avoiding the use of systemic therapy. In the STOMP and ORIOLE randomized trials, patients with oligometastatic castration-sensitive prostate cancer (omCSPC) demonstrated improved ADT-free survival and progression-free survival (PFS), respectively, following MDT, as compared to observation (5,6) (see Table 1). This approach has also shown promise with surgical MDT in a retrospective Mayo Clinic cohort (7). In a comparable manner, in the EXTEND trial, the combination of MDT with intermittent hormone therapy (ADT ± ARPI) significantly prolonged PFS compared to hormone therapy only while facilitating prolonged eugonadal testosterone intervals (8). Similarly, successful local MDT control rates have also been seen in oligometastatic castration-resistant prostate cancer (omCRPC) among men who remained on both ADT and ARPI therapy in the OPeRATIC trial (9). Most patients who receive radiotherapy (RT)-based MDT will eventually require ADT and other systemic treatments; however, it is notable that between 10% and 20% achieve long-term ADT-free remission (10,11).

Table 1

Summary of main findings from select systemic therapy and MDT clinical trials in patients with metastatic prostate cancer

Reference and agents Patients,
n		 bPFS Radiographic/metastatic PFS OS
Months
[95% CI]		 HR
(95% CI)		 P value Months
[95% CI]		 HR
(95% CI)		 P value Months
[95% CI]		 HR
(95% CI)		 P value
HORRAD (ISRCTN06890529)
   ADT + primary tumor RT 216 15
[11.8–18.2]		 0.78
(0.63–0.97)		 0.02 45
[40.4–49.6]		 0.9
(0.70–1.14)		 0.4
   ADT alone 216 12
[10.6–13.4]		 43
[32.6–53.4]
STAMPEDE (NCT00268476)
   Standard of care + primary tumor RT 1,032 17 [8–53] 0.76
(0.68–0.84)		 <0.0001 0.97
(0.86–1.10)		 48 [27–NR] 0.92
(0.80–1.06)		 0.266
   Standard of care alone 1,029 13 [6–33] 46 [27–NR]
STAMPEDE low metastatic burden (NCT00268476)
   Standard of care + primary tumor RT 410 0.59
(0.49–0.72)		 <0.0001 0.8
(0.63–1.01)		 0.68
(0.52–0.90)		 0.007
   Standard of care alone 409
STAMPEDE high metastatic burden (NCT00268476)
   Standard of care + primary tumor RT 553 0.88
(0.71–1.01)		 0.059 1.1
(0.95–1.28)		 1.07
(0.90–1.28)		 0.420
   Standard of care alone 567
ORIOLE (NCT02680587)
   SABR 36 NR 0.31
(0.13–0.75)		 0.002 0.19
(0.07–0.54)		 <0.001
   Observation 18 6.4
STOMP (NCT01558427)
   RT 31
   Observation 31
ORIOLE + STOMP meta-analysis
   RT 67 11.9
[8.0–18.3]		 0.44
(0.29–0.66)		 <0.001 0.81
(0.5–1.29)		 0.37
   Observation 49 5.9 [3.2–7.1]
MDT cohort ORIOLE + STOMP meta-analysis
   High-risk mutational signature 12 7.5 [5.9–NR] 0.53
(0.25–1.11)		 0.09 0.43
(0.20–0.95)		 0.04
   w/o high-risk mutational signature 30 13.4 [7.0–36]
PEACE1 (NCT01957436)
   Standard of care + abiraterone (with or w/o RT) 583 0.54
(0.41–0.71)		 <0.0001 5.72 years
[2.72–NR]		 0.82
(0.69–0.98)		 0.030
   Standard of care alone (with or w/o RT) 589 4.72 years
[2.59–NR]
ARASENS (NCT02799602)
   Darulotamide + ADT + docetaxel 651 NE 0.68
(0.57–0.80)		 <0.001
   Placebo + ADT + docetaxel 654 48.9
[44.4–NE]
VISION (NCT03511664)
   177Lu-PSMA-617 + BS/BSOC 551 8.7 0.40
(0.29–0.57)		 <0.001 15.3
[14.2–16.9]		 0.62
(0.52–0.74)		 <0.001
   BS/BSOC alone 280 3.4 11.3
[9.8–13.5]

177Lu, lutetium-177; ADT, androgen deprivation therapy; bPFS, biochemical PFS; BS/BSOC, best supportive/best standard of care; CI, confidence interval; HR, hazard ratio; MDT, metastasis-directed therapy; NE, not estimable; NR, not reached; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; SABR, stereotactic ablative radiotherapy; w/o, without.

The goal of therapy today is to personalize treatment in a way that extends the quantity and quality of life of each individual patient. In some cases, an intensification paradigm may delay the impact of aggressive cancer for those with overt, widespread metastatic disease. For example, combination therapies have repeatedly shown overall survival advantages in de novo metastatic CSPC in the PEACE-1 (ADT, abiraterone, and docetaxel) and ARASENS (ADT, darolutamide, and docetaxel) trials (12,13). Indeed, ongoing and recent studies in omCSPC and omCRPC are investigating therapy escalation by combining MDT with ADT, ARPI, radium-223, lutetium-177 (177Lu)-PSMA-617, and other systemic therapies (14-21). Additionally, although it seems clear that ADT (even a short course) does contribute to improved outcomes in many cases (22), a substantial number of patients achieve durable disease control with MDT alone (11). However, it is unknown whether—or in which patients—a de-intensification paradigm is warranted for oligometastatic disease.

De-intensification of systemic therapies offers clear benefits. Testosterone suppression can cause long-lasting deleterious physical and psychological side effects; avoiding hormone suppression, at least temporarily, may lead to fewer short-term side effects, increased quality of life, and improved cardiovascular outcomes associated with systemic therapies (23-28). Providers and patients may become more comfortable with avoiding or delaying systemic therapy if there were better tools for estimating the burden of micrometastases (tumor burden) beneath the imaging threshold.

Overcoming the limits of detection

While MDT is associated with excellent local control (29), distant recurrence is the primary cause of disease progression suggesting patients may present at diagnosis with subclinical metastatic lesions below the detection threshold of both conventional and advanced imaging (30). Metastatic lesions beneath a critical mass are not adequately visualized (31). If the total metastatic burden of disease (i.e., the aggregate volume of micrometastases) is spread across a sufficient number of lesions, the threshold of detection will not be reached. While some might argue that current PSMA-PET biomarkers perform adequately in assessing disease progression and treatment response, imaging-based approaches alone may not fully capture the complexity of this heterogeneous patient population. Given the imperfect sensitivity of PET imaging, there remains an unmet need for novel biomarkers to refine patient selection (32). Advanced imaging detection: (total metastatic burden)/(number of metastases).

Modalities that measure total metastatic burden—rather than visually detectable lesions—may overcome the limits of imaging. Blood-based tumor markers—which include tumor-derived extracellular vesicles (tdEVs), circulating tumor DNA (ctDNA), and circulating tumor cells (CTCs)—offer attractive solutions. These markers are highly sensitive, minimally invasive, agnostic to lesion number, and longitudinally reproducible. These datapoints could provide quantitative measures of “liquid tumor burden” (LTB) that may serve to risk stratify patients diagnosed with oligometastatic disease and guide treatment selection.

For instance, in a cohort of patients identified as oligometastatic on PET imaging, a blood-based test that can accurately estimate the total metastatic burden may help distinguish those most likely to benefit from early systemic therapy (Figure 1). While we presume many patients can benefit from MDT combined with systemic therapy in short order, some may benefit from a period of de-intensified treatment comprising MDT alone (Figure 2).

Figure 1 Comparison of imaging and blood-based modalities in estimating total metastatic burden in oligorecurrent prostate cancer patients. ctDNA, circulating tumor DNA.
Figure 2 Role of blood-based biomarkers in identifying true oligometastatic disease and informing treatment de-escalation or intensification. (A) Benefit of MDT combined with systemic therapy versus MDT alone based on true oligometastatic burden. (B) Potential of blood biomarkers to overcome the detection limits of conventional and advanced imaging. bTBI, blood tumor burden index; LOD, limit of detection; MDT, metastasis-directed therapy; SBRT, stereotactic body radiotherapy.

While such a blood test has not yet reached clinical use, promising findings demonstrated clinical potential of a tdEV-based blood test to complement PET imaging for the diagnosis of omPC. In a cohort of heavily pre-treated patients diagnosed with omCRPC (≤3 metastasis) on 11C-choline PET imaging, pre-treatment levels of PSMA- and six-transmembrane epithelial antigen of prostate 1 (STEAP1)-positive tdEVs were predictors of disease recurrence (33). Patients with high tdEV levels were at greater risk of distant metastatic progression than those with low tdEV levels. This suggests that factors other than imaging may be prognostically important and help us increase our accuracy estimating disease burden and therefore identifying treatable metastases. A retrospective pooled analysis of ORIOLE and STOMP measuring tdEVs in omCSPC treated with stereotactic ablative RT (SABR) reached similar conclusions (34). In the SABR arm, biochemical PFS (bPFS) was 11.9 months. Patient stratification based on pre-treatment levels of tdEVs (defined as positive for PSMA) showed bPFS of 24.3 and 5.9 months for patients with low and high tdEV levels, respectively (P=0.005). Similarly, the radiographic PFS (rPFS) of the entire cohort of SABR-treated patients was 29.6 months. rPFS was 36 and 11.1 months for patients with low and high tdEV levels, respectively. This novel blood-based quantification of subclinical tumor burden may guide clinicians on whether to include systemic therapy in addition to MDT in oligometastatic cancers.

Future studies

Prospective studies are warranted to test the role of blood biomarkers, perhaps most usefully in the context of the multivariate analyses embedded into prospective trials. Moreover, additional prognostic biomarkers need to be tested to determine which are most predictive of clinically relevant outcomes. These promising findings support the potential of a tdEV blood test to identify a subset of oligometastatic disease in patients who would benefit from metastasis-directed RT alone. If tdEV should reflect the total volume of disease or its risk for multifocal progression in the near future, then results will better inform the decision of whether (or not) to offer concurrent systemic therapy. This may augment molecular profiling and advanced imaging modalities such as choline- and PSMA-PET in informing care.

In parallel, CTCs and ctDNA are also being studied in this context. Both tumor markers have shown prognostic and predictive value in metastatic prostate cancer (35-38), but their detection in the oligometastatic state may pose some challenges due to low abundance of these analytes in the blood (39).

Additional clinical trials investigating novel approaches for this patient population are currently underway across the globe. These include the study of short-course ADT in addition to MDT (NRG-GU011 trial, NCT05053152), as well as several trials exploring MDT in combination with different systemic therapies (“escalation approaches”) such as: KNIGHTS (NCT06212583), which adds niraparib/abiraterone; DIRECT (NCT05404139), which adds 8 months of enzalutamide; SBRT-AMICO (NCT05915442), which adds a combination of a CD73 inhibitor (quemliclustat), A2AR/A2BR inhibitor (etrumadenant), and anti-PD-1 (zimberelimab); POSTCARD (NCT03795207), which adds durvalumab (anti PD-L1); POPSTAR II (NCT05560659) and LUST (NCT05893381), which both add 177Lu-PSMA-617; and ProstACT TARGET (NCT05146973), which adds 177Lu-TLX591 (radiolabeled PSMA-targeting antibody). We believe, however, that future clinical trials could benefit from novel methods for assessing volume of disease, including, potentially, stratification based on blood-based tumor burden. We advocate for a clinical trial comparing systemic therapy (with ADT and ARPI or other well-established systemic therapies) to observation in men with omCSPC treated with MDT. The hypothesis is that high extracellular vesicle (EV) levels reflect significant non-visible tumor burden, and such patients may benefit from early and aggressive therapy, while patients with low EVs may have a durable response to MDT alone. This is the basis of the ongoing DIVINE/DEVIATE clinical trial (NCT06378866) and other de-escalation trials currently in development.

Conclusions

omPC is a clinically heterogeneous state that defies conventional treatment paradigms. While MDT can delay or even avoid systemic therapy in select patients, most will eventually require subsequent systemic intervention. Blood-based biomarkers that assess LTB, such as tdEVs, ctDNA, and CTCs, provide a promising means to refine patient selection and tailor treatment intensity beyond what imaging alone can offer. Ongoing and future clinical trials incorporating these tools may help establish which patients benefit most from MDT alone versus combination strategies. Ultimately, personalizing treatment by integrating novel biomarkers with imaging and other clinical parameters may help optimize outcomes for patients with oligorecurrent prostate cancer.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-24-187/prf

Funding: This work was supported by the National Cancer Institute (to J.J.O.) (No. K12 CA90628-23), the Prostate Cancer Foundation (to J.J.O.) (No. YIA), and the Department of Defense (to J.J.O. and F.L.) (No. HT9425-24-1-9622).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-24-187/coif). D.S.C. receives advisory boards fees from Janssen (to institution), Novartis (to institution) and Abdera (to institution); honoraria for educational purposes from DAVA Oncology, Curio, Targeted Oncology, MJH Life Sciences, GU Oncology Now, IDEOlogy and International Centers for Precision Oncology; and research funding from Janssen (to institution) and Novartis [to institution (in progress)]. J.A. receives honoraria from Bayer and Blue Earth Diagnostics. S.P. receives royalties from Nanotics (to institution), and stocks and other ownership interests from Natera and Guardant Health. O.S. receives consulting fees from Astellas Pharma, Progenics, Swiss Rockets, Abdera, Actinium Pharma, AdvanCell, Alpha9, ArtBio, AstraZeneca, Bayer, Clarity, Convergent, Curium, ITM, JNJ, Merck, Modex, Norroy, NorthStar, Novartis, Nucleus Biopharma, Precede, Telix and Wren Laboratories; and stock or stock options from Cardinal Health, AbbVie, United Health Group, Curadh, Clarity, Ratio, Pfizer, Lilly, Telix, AdvanCell, ArtBio, Convergent and Asta. B.J.S. receives research funding from Varian Medical Systems (to institution), and honoraria from Kansas Society of Clinical Oncology. A.A.C. receives research support from Illumina, Roche, and Tempus; consulting fees from Guardant Health, Caris, Geneoscopy, Illumina, Myriad Genetics, Invitae, Daiichi Sankyo, AstraZeneca, AlphaSights, DeciBio and Guidepoint; honoraria from Agilent and Illumina; has patent filings related to cancer biomarkers; has stock options in Geneoscopy, and ownership interests in Droplet Biosciences, CytoTrace Biosciences, and LiquidCell Dx. P.S.C. has patent filings related to cancer biomarkers. R.P. receives travel support from Novartis and has an uncompensated relationship with Veracyte. F.L. receives royalties or licenses from NaNotics LLC and Early is Good, and consulting fees from Nanotics LLC and Mursla Bio. J.J.O. receives research support from the Prostate Cancer Foundation (No. YIA), Department of Defense (No. HT9425-24-1-9622), and National Cancer Institute (No. K12 CA90628-23) and he is PI of a study with drug-only support from Genentech. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Muniz M, Childs DS, Andrews J, Mahmoud AM, Park S, Sartor O, Kase AM, Riaz IB, Stish BJ, Chaudhuri AA, Chauhan PS, Phillips R, Lucien F, Orme JJ. Deferral of systemic therapy in patients with oligorecurrent prostate cancer treated with metastasis-directed radiotherapy. Ann Transl Med 2025;13(3):29. doi: 10.21037/atm-24-187

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