Metastasis-directed therapy in oligoprogressive prostate cancer: current evidence and future directions

Introduction

Prostate cancer is one of the most commonly diagnosed malignancies in men worldwide and remains a leading cause of cancer mortality (1). In the metastatic setting, systemic treatment intensification has extended survival and prolonged periods of disease control, such that many patients remain on an effective backbone regimen for longer than in prior eras (2-8). In parallel, advances in contemporary molecular imaging—particularly prostate-specific membrane antigen (PSMA) positron emission tomography (PET)—have increased sensitivity for detecting metastatic disease and frequently alter staging and management compared with conventional imaging, increasing recognition of small-volume metastases and focal patterns of failure (9). These developments have led to greater recognition of limited-site progression, or oligoprogression, as a common and increasingly consequential clinical scenario, often prompting discussion about whether to incorporate metastasis-directed therapy (MDT), adjust systemic treatment, or prioritize supportive-focused care based on symptoms, treatment burden, and patient goals.

Historically, oligometastatic and oligoprogressive prostate cancer have been defined using conventional imaging [computed tomography (CT), magnetic resonance imaging (MRI), and nuclear medicine bone scan] as the presence of 1–5 metastatic lesions (10). However, this definition suffers from discordance with contemporary practices and preferential use of PSMA PET in initial staging and identifying recurrences. PSMA PET identifies a greater burden of disease compared with conventional imaging and frequently results in stage migration. Recent Journal of the National Comprehensive Cancer Network (JNCCN) guidance reflects these changes, defining oligoprogressive disease as limited-site progression, most commonly ≤3–5 lesions on conventional imaging, but potentially higher (up to ~10 lesions) when defined by PSMA PET, in the setting of otherwise controlled systemic disease, with the critical requirement that all progressing sites remain amenable to safe MDT (9,10).

This pattern is thought to reflect focal outgrowth of treatment-resistant subclones under ongoing systemic selective pressure (11-13). While this classic, on-therapy oligoprogression parallels paradigms described in other solid tumors (14), prostate cancer is increasingly characterized by an off-therapy oligoprogressive state also termed repeat oligorecurrence (15). This is a result of patients with oligometastatic disease increasingly being treated with MDT alone or MDT plus a limited course of systemic therapy to defer continuous androgen deprivation therapy (ADT). In this context, some patients develop serial limited-site recurrence off systemic therapy, for which repeat MDT is often considered to extend systemic therapy-free intervals (16,17).

Therefore, oligoprogression in prostate cancer encompasses biologically and clinically distinct states with differing treatment goals. In the castration-sensitive setting, local therapy is often aimed at delaying initiation or re-initiation of ADT and mitigating the long-term effects of testosterone suppression (Figure 1A). In the castration-resistant setting, the goal is to ablate resistant clones while maintaining patients on otherwise effective systemic therapy, thereby prolonging disease control without immediately incurring the toxicity, cost, or quality-of-life consequences of systemic escalation. Within castration-resistant prostate cancer (CRPC), it is also useful to distinguish between patients with limited-volume oligometastatic disease amenable to consolidation of all known sites with MDT (Figure 1B) and patients with more widespread disease who progress at only a small number of sites while the remainder of disease remains controlled on systemic therapy (Figure 1C). In this review, we summarize the biologic rationale, clinical evidence, and future directions for local therapy in oligoprogressive prostate cancer in both the castration-sensitive and castration-resistant settings.

Figure 1 Oligoprogressive disease states. (A) Castration-sensitive oligoprogressive disease, in which new limited-site recurrence following prior metastasis-directed therapy with or without systemic therapy may be treated with repeat metastasis-directed therapy. (B) Castration-resistant oligometastatic disease, in which all known sites of disease are consolidated with metastasis-directed therapy while androgen deprivation therapy with or without an androgen receptor pathway inhibitor is continued. (C) Castration-resistant oligoprogressive disease, in which a limited number of progressing lesions are treated with metastasis-directed therapy while the remaining disease remains controlled on androgen deprivation therapy with or without an androgen receptor pathway inhibitor. ADT, androgen deprivation therapy; ARPI, androgen receptor pathway inhibitor.

Metastatic castration-sensitive prostate cancer (mCSPC)

Although continuous ADT with an androgen receptor pathway inhibitor (ARPI) remains a cornerstone of treatment for mCSPC, MDT has increasingly been incorporated in the oligometastatic setting as a means of delaying the need for continuous hormone suppression and its associated toxicities. Early evidence supporting an ADT-sparing approach came from the STOMP trial, which randomized 62 patients with choline PET-detected metachronous oligometastatic castration-sensitive prostate cancer (omCSPC) to MDT or observation (16). This study demonstrated that MDT significantly prolonged ADT-free survival compared with observation (21 vs. 13 months) without compromising quality of life, thereby supporting a role for MDT in deferring systemic therapy initiation. Notably, 35% of patients randomized to the MDT arm subsequently developed repeat oligorecurrence and underwent additional courses of MDT, further postponing the need for systemic therapy and providing some of the earliest prospective evidence supporting a serial MDT strategy in CSPC.

These observations were reinforced by the phase II ORIOLE trial, which similarly randomized 54 patients with conventionally detected metachronous omCSPC to MDT or observation (17). At 6 months, progression was substantially less frequent among patients treated with MDT than among those managed with observation (19% vs. 61%), further supporting the ability of MDT to delay disease progression and defer escalation to systemic therapy. Collectively, these randomized phase II data established MDT as a novel ADT-sparing approach in selected men with metachronous omCSPC. However, these trials did not enroll patients with de novo omCSPC and relied on surrogate endpoints rather than definitive survival outcomes. Whether MDT in de novo omCSPC provides oncologic benefit is under investigation (18).

While MDT alone remains an attractive option for selected patients, integration of systemic therapy with MDT remains an active clinical question and has been the focus of a recent dedicated review (19). Strategies under investigation include short-course ADT, intermittent or continuous hormone therapy combined with MDT, ARPI- or chemotherapy-based intensification in selected patients, triplet approaches in de novo mCSPC, and PSMA-targeted radioligand therapy. In the metachronous oligorecurrent setting, a central goal of these approaches is to improve the durability of disease control while preserving the possibility of subsequent treatment-free intervals. The RADIOSA trial provided the first randomized evidence directly supporting this approach. In this randomized phase II trial, 105 men with metachronous omCSPC were randomized to stereotactic body radiotherapy (SBRT) alone or SBRT plus 6 months of ADT (20). With a median follow-up of 31 months, the addition of ADT significantly improved median clinical progression-free survival (PFS) from 15.1 months with SBRT alone to 32.2 months with combined therapy [hazard ratio (HR) 0.43, 95% confidence interval (CI): 0.26–0.72; P=0.001]. Among patients who progressed, repeat oligorecurrence remained common, occurring in 56% of patients treated with SBRT alone and 72% of those receiving combined therapy, supporting the feasibility of repeat MDT even after initial intensification. The addition of MDT to intermittent ADT (iADT) has also been shown to improve PFS as well as eugonadal PFS in the phase II EXTEND trial. Patients were randomized to MDT and iADT versus iADT, with a planned hormone therapy break at 6 months. At a median follow up of 22 months, PFS was significantly improved in the combined therapy arm compared to the ADT alone arm (HR 0.25; 95% CI: 0.12–0.55; P<0.001) (21). Notably, the EXTEND trial did not report the proportion of patients treated with further MDT for repeat oligorecurrence.

Other combined approaches with MDT have also been shown to improve oncologic outcomes. The LUNAR trial, which randomized 92 patients with omCSPC to MDT alone or MDT plus 2 cycles of ¹⁷⁷Lu-PNT2002, showed that addition of ¹⁷⁷Lu-PNT2002 to MDT significantly improved PFS (17.6 vs. 7.4 months; P<0.0001) and prolonged median hormonal therapy-free survival (24.3 vs. 14.1 months; P<0.001) (22). Importantly, repeat MDT remained feasible after initial treatment, with approximately 40% of patients undergoing salvage MDT at progression, approximately half without the addition of hormonal therapy. These findings suggest that adding short-course systemic therapy may improve the durability of an MDT-based strategy while preserving the option for subsequent salvage MDT in selected patients. This concept is being further tested in the ongoing phase III PSMA-DC trial (NCT05939414), which evaluates SBRT with or without ¹⁷⁷Lu-vipivotide tetraxetan in patients with PSMA-positive oligometastatic prostate cancer defined by PSMA PET. Additional phase II data from BULLSEYE also support continued investigation of PSMA-targeted radioligand therapy in oligometastatic hormone-sensitive prostate cancer (23). Several additional clinical trials have evaluated limited-duration systemic therapy, though data on patterns of failure/oligoprogression following initial therapy are limited (Table 1) (21,23-26).

Although these studies are encouraging, there are several limitations. The major trials supporting integrating MDT with existing systemic approaches (including RADIOSA, EXTEND, and LUNAR) are phase II trials with modest sample sizes, short to intermediate follow-up, and endpoints such as clinical PFS, hormonal therapy-free survival, and repeat MDT feasibility rather than overall survival (OS). ADT-free or hormonal therapy-free survival is clinically meaningful because it reflects avoidance of treatment toxicity and quality-of-life burden, but it is also partly dependent on physician and patient decision-making regarding when to initiate systemic therapy. As such, these endpoints may be more susceptible to practice variation than radiographic PFS or OS.

In addition to systemic intensification, radiation volumes may also influence outcomes. The phase II PEACE V-STORM trial randomized 190 patients with PET-detected pelvic nodal oligorecurrence to MDT or elective nodal radiotherapy (ENRT); the study showed a 13% absolute improvement in 4-year metastasis-free survival with ENRT (76% vs. 63%; HR 0.62) as well as fewer pelvic nodal relapses (8% vs. 29%) (27). These data suggest that, at least for limited nodal recurrence, broader-field treatment may improve regional control and reduce distant metastasis beyond lesion-directed therapy alone, although how this approach influences the feasibility of future salvage MDT remains to be defined.

Although no randomized trial has specifically tested repeat MDT for repeat oligorecurrent CSPC, the collective findings from the aforementioned prospective randomized studies suggest that a serial MDT strategy may meaningfully extend time off continuous ADT in appropriately selected patients. Several other studies also support this approach. In a prospective study by Decaestecker et al. of 50 men treated with SBRT, 75% of patients who had clinical progression developed repeat oligorecurrence rather than diffuse progression, with a median ADT-free survival of 25 months (28). The subsequent phase II single-arm TRANSFORM trial provided longer-term support for serial MDT in a larger cohort of 199 men with omCSPC treated with SBRT; 76.4% were ADT-naïve at baseline and 50.8% ultimately received at least one additional course of SBRT (29). Five-year treatment escalation-free survival (TE-FS), defined as survival without the need for additional systemic therapy or other treatment escalation, was 21.7% overall and 25.4% in the ADT-naïve subgroup, with 18.9% of evaluable patients remaining free from treatment escalation at a median follow-up of 67.9 months. Importantly, the ability to deliver repeat SBRT courses was associated with particularly favorable outcomes, as receipt of a total of three SBRT courses (HR 0.57, 95% CI: 0.38–0.86; P=0.007) or four courses (HR 0.30, 95% CI: 0.17–0.54; P<0.001) was associated with significantly prolonged TE-FS. Although TRANSFORM was not restricted to a purely castration-sensitive population, these findings provide compelling prospective support for the concept that selected patients can experience repeated limited-site relapse amenable to further SBRT, thereby delaying systemic treatment escalation.

Patterns of recurrence following MDT further support this strategy. Across multiple series, progression after MDT frequently remains limited in extent, permitting additional salvage MDT and prolonging ADT-free intervals. For example, Berkovic et al. treated 24 patients with repeated salvage SBRT and reported a median ADT-free survival of 38 months; notably, 11 and 3 patients underwent second and third salvage treatments, respectively, with 2-year local control of 100% and no grade 3 toxicity (30). Kalinauskaite et al. reported repeat oligorecurrence in 64% of patients (median two new metastases, range 1–5), with 48% undergoing a second course of PSMA-PET-guided SBRT after a median interval of 17 months (31). Similarly, Kwon et al. evaluated 25 patients treated with two consecutive courses of SBRT, observing a median ADT-free survival of 23.2 months after the second course, with response to the first SBRT predicting improved PFS (HR 0.36, 95% CI: 0.00–0.42; P=0.008) (32). Longer-term data from Mohan et al. likewise suggest that repeat curative-intent salvage treatment can substantially prolong ADT-free trajectories: among 103 patients treated with upfront SBRT without ADT, 32% underwent further curative-intent radiation after first biochemical failure, leaving 39% completely ADT-free at 5 years (33).

Emerging data suggest recurrences may exhibit distinct and predictable anatomical patterns based on initial sites of disease at time of initial MDT. In a pooled nodal SBRT series from Ost et al., 88% of patients still had ≤3 metastases at progression, 68% of relapses remained nodal, and median time to palliative ADT was 44 months (34). This predilection for compartment-specific failure was corroborated by Deek et al. in a cohort of 258 omCSPC patients treated with MDT, where the majority of patients with initial bone disease progressed in the bone (86.5%), whereas those with initial nodal disease commonly progressed in the lymph nodes (64.5%) (35). This work also identified three principal patterns of overall progression: durable disease control lasting more than 18 months (40.9%), repeat oligorecurrence involving 3 or fewer lesions (36.0%), and polyrecurrent (23.1%). Subsequent genomic analysis revealed that pathogenic somatic RB1 alterations were associated with an increased risk of polyprogression, whereas TP53 mutations correlated with a lower likelihood of durable long-term control (36). Importantly, these patterns carry prognostic significance: patients who developed repeat oligorecurrence mCSPC had superior 3-year OS from the time of recurrence compared with those who developed polyrecurrent disease (91% vs. 71%, P=0.005). Although a growing biomarker literature has emerged in omCSPC, including studies of PSMA-positive extracellular vesicles, circulating tumor cells, T-cell receptor unique productive rearrangements, pathogenic genomic alterations, and digital pathology artificial intelligence, these data largely derive from de novo omCSPC rather than repeat oligorecurrent CSPC (18,37-40). At present, no biomarker has been validated to specifically guide outcomes or treatment selection for patients who develop repeat oligorecurrent CSPC after prior MDT with or without limited-duration systemic therapy. As such, repeat MDT decisions in this setting remain driven primarily by clinical factors, imaging-defined extent of progression, prior treatment history, and patient goals.

While not strictly included in the category of “oligoprogression”, de novo synchronous oligometastatic CSPC is also an area in which the role of MDT is evolving. Recent National Comprehensive Cancer Network (NCCN) guidelines have shifted to reflect changes in practice landscape to accommodate use of MDT in the de novo setting (10). For these patients, the backbone of treatment remains intensified systemic therapy with consideration for external beam radiation therapy to the prostate in select patients with low volume disease (41,42). The observation that prostate-directed therapy can improve outcomes even in the context of enhanced systemic therapy supports the hypothesis that more broad consolidation and ablation of visible disease, may provide additional benefit in carefully selected patients. Similar to the metachronous state, total consolidation of low-volume de novo oligometastatic disease may induce a more durable response and lead to improved oncologic outcomes and potentially time off of systemic therapy.

Several smaller prospective trials have suggested safety and potential oncologic benefit of adding MDT to conventional approaches in de novo omCSPC. The phase II total eradication therapy (TET) trials, which used a trimodality approach of radical prostatectomy, 1–2 years of ADT, intensified therapy with docetaxel +/− abiraterone, prostate bed RT, and SBRT to ≤5 osseous or nodal metastatic lesions, showed durable prostate-specific antigen (PSA) response after testosterone recovery in 24/30 (80%) of evaluable patients (43). Similarly, the phase II single-arm SOLAR trial, which added MDT to intensified systemic therapy (leuprolide, apalutamide, and abiraterone acetate plus prednisone), found that 20/24 (83%) patients were free from progression at a median follow-up of 31 months (25). Notably, these studies do not report on patterns of failure (oligoprogression vs. polyprogression) after a total consolidative approach.

There are several larger ongoing randomized trials designed to address the benefit of MDT in addition to enhanced systemic therapy. These include phase II studies METANOVA (NCT06150417) and TERPS (NCT05223803), as well as phase III studies STAMPEDE 2 (NCT06320067), START-MET (NCT05209243), OLIGO-PRESTO (NCT04115007), PLATON (NCT03784755).

Timing and sequencing of systemic therapy relative to MDT is also a critical issue that is the focus of the phase II DIVINE (NCT06378866) study, which is randomizing patients (including with de novo disease) with 1–5 metastases on conventional imaging to receive up front ADT + ARPI with SBRT versus SBRT with delayed systemic therapy at time of radiographic progression.

Metastatic castration-resistant prostate cancer (mCRPC)

Adoption of MDT into consensus treatment recommendations for mCRPC is a relatively recent development (NCCN v3.2026) (10). For years, the mainstays of therapy for men who developed castration resistance have been chemotherapy and ARPIs (44-47). Given the median OS after development of castration-resistance is less than 2 years (48), mCRPC has been regarded as a fundamentally aggressive, systemic disease state requiring systemic solutions (49). However, emerging data increasingly support the existence of clinically meaningful limited-site states within mCRPC. These are most often grouped into two related but distinct scenarios: oligometastatic CRPC (termed metachronous oligoprogression) in which patients have limited metastatic burden at the time CRPC emerges, and either repeat oligoprogression or induced oligoprogression, in which patients develop progression at only a small number of sites while the remainder of disease remains controlled. In newly resistant limited-volume disease, MDT is generally used to consolidate all known sites in conjunction with systemic therapy. Conversely, in oligoprogression, progression-directed MDT is used to ablate the progressing resistant clones while relying on the ongoing systemic regimen to control the remaining stable disease.

Oligometastatic CRPC/metachronous oligoprogression

The most compelling evidence to support the addition of MDT to systemic therapy in mCRPC comes from two randomized phase II trials (Table 2). The ARTO trial randomized 157 patients with 1–3 nodal or bone oligometastatic sites defined on either conventional imaging or molecular imaging (choline or PSMA PET) to ADT plus abiraterone acetate/prednisone (AAP) plus or minus SBRT to all visible lesions (50). The primary endpoint was rate of biochemical response (defined as ≥50% from baseline measured at 6 months) favored the SBRT arm (92% vs. 68.3%). Additionally, patients on the SBRT arm had a significant improvement in composite PFS (HR 0.35; 95% CI: 0.21–0.57; P<0.001) with a median PFS of 17 months vs. not reached. The secondary endpoints of OS and prostate cancer-specific survival (PCSS) were also recently reported (51). The SBRT arm demonstrated significant improvement in median OS (not reached vs 50 months; HR 0.55, 95% CI: 0.33–0.92, P=0.02) and PCSS (not reached both arms; HR 0.37, 95% CI: 0.18–0.78, P=0.008). There were no significant differences in grade 2 or higher adverse events or overall events between the two arms.

Similarly, the GROUQ-PCS 9 trial randomized 102 men who progressed on ADT to 1–5 sites of disease (on conventional imaging only, excluding only brain metastases) to ADT plus enzalutamide plus or minus SBRT to all identified lesions (52). The addition of SBRT improved median radiographic progression-free survival (rPFS) from 2.3 to 4.6 years (HR 0.48; 95% CI: 0.27–0.86; P=0.014). Toxicity rates were comparable in both arms. In combination, these two trials provide randomized phase II evidence supporting the feasibility and potential clinical benefit of layering SBRT onto systemic therapy in selected patients oligometastatic mCRPC. However, both ARTO and GROUQ-PCS 9 were relatively small phase II trials, enrolled selected patient populations, and included patients with limited prior exposure to contemporary systemic intensification. Thus, while the results are provocative, prospective phase III validation is needed to confirm the magnitude and durability of benefit of MDT in the modern systemic therapy era.

More recently, Tang et al. performed a systematic review and individual patient data meta-analysis (WOLVERINE) of 6 major trials, including ARTO, that randomized patients with oligometastatic prostate cancer to standard of care (SOC) versus SOC + MDT. The meta-analysis included 472 patients with a median follow-up of 40.7 months (53). Among these cohorts, 46% of the SOC and 38% of the SOC + MDT were at baseline castration-resistant. Taking into consideration variability in imaging assessment of oligometastasis across trials and the SOC for each trial, the study reported a significant PFS benefit of MDT in both the CSPC (HR 0.51; 95% CI: 0.38–0.68) and the CRPC (HR 0.45; 95% CI: 0.30–0.66) cohort. However, WOLVERINE included a heterogeneous population, with variation in castration state, imaging modality, systemic therapy backbone, use of ADT, MDT approach, and trial endpoints. These factors limit definitive disease-state-specific conclusions and suggest that the findings should be interpreted as supportive of MDT as a broad therapeutic principle rather than as conclusive evidence for any single clinical scenario. Based on the aforementioned prospective phase II evidence and WOLVERINE meta-analysis, the NCCN guidelines have recently updated to include MDT as a preferred approach in oligometastatic castration-resistant prostate cancer (omCRPC) when used up front in conjunction with recommended first-line systemic therapies.

These prospective findings are further supported by several prospective and retrospective non-randomized series, which suggest that MDT can prolong biochemical or clinical PFS and delay next-line systemic therapy in selected patients with oligometastatic mCRPC. In a single-arm phase II study of 89 patients with choline PET-defined omCRPC treated with SBRT, Zhang et al. reported median OS of 29.3 months, with 1- and 2-year OS rates of 96% and 80%, respectively, and no grade 3 or higher toxicity (54). High baseline levels of tumor-reactive T cells and effector memory T cells were associated with improved PFS. Increases in tumor-reactive T cells at day 14 were associated with superior OS.

A multicenter retrospective study by Triggiani et al. was one of the earliest large studies to report durable outcomes for MDT in newly developed omCRPC. For 86 patients with oligometastasis (defined on choline PET or conventional imaging) who did not receive prior intensified systemic therapy, SBRT to all visible lesions resulted in a median new metastasis-free survival of 12.3 months. Notably, 30% of patients developed additional oligoprogression amenable to SBRT, resulting in a median time to next systemic therapy of 21.8 months (55). In a multi-institutional retrospective study, Chamois et al. evaluated 51 patients with PET-defined omCRPC treated with MDT. The 3-year OS rates were excellent (>80%) for patients who received MDT or MDT with castration-resistant systemic treatment up front for new oligometastases. In contrast, for patients who had prior oligometastasis that developed resistance to ARPI (given during the hormone-sensitive phase) at time of CRPC, the 3-year OS was 44%, suggesting a more aggressive natural history for ARPI-resistant clones (56). Nikitas et al. also retrospectively evaluated MDT for omCRPC and reported median time to next-systemic therapy of 29 months and a 4-year OS of 69% (57). Interestingly, patients who changed systemic therapy with the start of MDT had significantly longer PFS than those who did not change systemic therapy (49.3 vs. 12.9 months, P=0.001). Finally, an institutional series by Lohaus et al. demonstrated significant PSA response for 73% of 15 patients with omCRPC treated with SBRT or conventional pelvic RT, with a mean bPFS of 17.9 months (58). Although these studies are limited by single-arm or retrospective design and some heterogeneity in imaging and systemic therapy context, collectively they support the existence of a clinically meaningful omCRPC subgroup in whom local therapy may prolong disease control.

Though these studies have established a role for MDT in omCRPC, there are important limitations to note. Both ARTO and PCS 9 enrolled men with newly developed CRPC, which may be inherently different than men with more advanced disease who have failed several lines of systemic therapy. Prior treatment intensification with docetaxel or ARPI occurred in only seven patients in ARTO and was excluded in PCS 9, reflecting the fact that standards of care for mCSPC changed during and after these studies accrued. Therefore, while the use of MDT to postpone next-line systemic therapy is becoming a more mainstream approach in newly diagnosed mCRPC, the effectiveness of MDT in more advanced mCRPC requires further study in randomized trials. Volume of disease is also an important consideration that these trials do not address fully. With the prevalence of PSMA PET imaging used to define disease recurrence, future studies are needed to address whether consolidation of micro-metastatic disease with MDT is critical as part of first-line management in omCRPC. Finally, the role of MDT in omCRPC needs to be validated in larger phase III trials. There are several ongoing phase III trials in this space such as DECREASE (NCT04319783), PILLAR (NCT03503344), PEACE8 (NCT06276465), and FORCE (NCT03556904).

Oligoprogressive CRPC/repeat and induced oligoprogression

Oligoprogressive CRPC specifically refers to a scenario where a patient on active systemic therapy, most commonly an ARPI, develops progression at ≤3–5 sites while the remaining disease burden remains stable. Several recent single-arm phase II trials have further characterized the efficacy and safety of SBRT for this population (Table 2). The TRAP trial treated 81 men with ≤2 oligoprogressive sites on an ARPI with SBRT while continuing systemic therapy (59). This demonstrated a median PFS of 6.4 months and a median time to next therapy of 27 months. The phase II RADIANT trial treated 32 men with up to 5 sites, reporting that 55.1% remained on the same systemic therapy at 1 year (60). The cumulative incidence of grade 2 toxicity was 25.0% at 1 year and no grade 3+ toxicities were reported. Similarly, the MEDCARE trial enrolled 20 patients with 38 oligoprogressive lesions treated with progression-directed therapy. At a median follow-up of 28 months, median next-line systemic treatment-free survival was 17 months with 35% free from next-line systemic therapy at 2 years (61).

These prospective results are supported by several retrospective series. Deek et al. evaluated 68 patients and found that MDT was associated with longer time to next intervention (14.9 vs. 8.8 months, P=0.025) and longer distant metastasis-free survival (12.7 vs. 8.9 months, P=0.045) compared to changing systemic therapy alone (62). Similar results were demonstrated by Lee et al. who evaluated 40 patients treated with or without MDT revealing a median time to failure of systemic therapy of 30.2 vs. 14.9 months respectively (63). More recently, Bauersachs et al. evaluated 55 patients with PSMA-PET detected oligoprogression and demonstrated MDT was associated with significantly improved 3-year OS vs. SOC (93% vs. 63%, P=0.01) (64). These comparative findings are supported by numerous institutional series which consistently demonstrate that progression-directed SBRT provides a median next-line systemic therapy-free survival ranging from 10 to 36 months (12,55,65-69). For example, Franzese et al. and Ingrosso et al. both reported median systemic therapy-free survivals exceeding 15 months in cohorts of men treated for up to 5 progressive lesions (12,65). A study evaluating a subset of patients with nodal oligoprogression reported durable control with 2-year next-line systemic therapy-free survival rates approaching 68% (70). Across these studies, local control typically exceeds 90%, and grade 2+ toxicities are rare.

Several studies have also identified clinical and imaging biomarkers that may help refine selection for progression-directed therapy in oligoprogressive CRPC. In a cohort of 59 patients with oligoprogressive CRPC treated with progression-directed therapy, PSA doubling time of at least 6 months was associated with higher PSA50 response rates, longer PFS, and longer time to next treatment (71). A separate retrospective series of 35 patients similarly found that time to oligoprogression of at least 1 year from initiation of the most recent systemic therapy was independently associated with longer PFS on multivariable analysis (HR 0.35, 95% CI: 0.13–0.94; P=0.038), with a median PFS of 8.0 months and PSA50 response rate of 57.1% (72). Additional series have reinforced the importance of response and disease tempo: Lee et al. found that patients treated with progression-directed therapy had lower PSA nadirs, higher rates of PSA50 decline, and longer time to failure of first-line systemic therapy, whereas Onal et al. reported that oligoprogression within 6 months of starting ARPI therapy and higher post-treatment PSA were independently associated with worse PFS and PCSS (63,73). Imaging remains central to selection, with PSMA PET used to determine whether progression remains focal and amenable to complete ablation; however, PSMA-low or discordant disease may limit reliance on PSMA PET alone in patients with suspected dedifferentiated or AR-indifferent progression (64,74,75). Finally, emerging tissue genomic data suggest that a high-risk alteration signature involving AR, TP53, RB1, or PTEN may identify patients with more aggressive resistant biology, but these data remain early and are not yet validated for routine treatment selection (76).

Collectively, these prospective and retrospective data suggest that carefully selected men with oligoprogressive CRPC can achieve meaningful periods of disease control and prolong the benefit of otherwise active systemic therapy with SBRT. Randomized phase III data are needed to refine patient selection and define the magnitude of benefit. Several ongoing randomized trials are evaluating this question, including the phase II trials SECURE (NCT06927635) and OLYMPIAN (NCT07038304) and the phase III continuation of the MEDCARE trial (NCT06585007).

Conclusions

The management of metastatic prostate cancer is shifting from a uniform systemic approach to a nuanced strategy incorporating local therapy for limited progression. In the castration-sensitive setting, MDT—either alone or with short-course systemic therapy—may preserve quality of life by delaying and/or limiting time on ADT. Following initial MDT, some patients experience subsequent oligoprogression, permitting serial salvage treatments which may further extend treatment-free intervals in selected cases. In the castration-resistant setting, focal progression of resistant clones against a background of otherwise stable systemic disease creates a therapeutic rationale for MDT; however, the supporting evidence remains largely phase II or non-randomized. Trials such as ARTO and PCS 9 provide provocative randomized phase II data supporting MDT in oligometastatic CRPC, while studies such as TRAP, RADIANT, and MEDCARE suggest that ablating focal progressive sites may prolong the durability of an existing systemic regimen and delay treatment escalation. Moving forward, the integration of molecular imaging and genomic biomarkers will be essential to differentiate true oligoprogression from occult polyprogression. Although current evidence has influenced guideline consideration of MDT in selected patients, ongoing prospective phase III trials will be critical to define its magnitude of benefit, optimal sequencing with systemic therapy, and ultimate role as a standard component of care across castration-sensitive and castration-resistant disease states.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Michael T. Milano, Tithi Biswas, Charles B. Simone II, and Simon S. Lo) for the series “Oligoprogressive Disease in Cancer” published in Annals of Palliative Medicine. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-2026-0041/prf

Funding: This study was supported by the Prostate Cancer Foundation (to P.A.S.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-2026-0041/coif). The series “Oligoprogressive Disease in Cancer” was commissioned by the editorial office without any funding or sponsorship. P.T.T. reports research support from the NIH/NCI (R01CA271540 and U54CA273956); holds patent no. 9114158, ‘Compounds and Methods of Use in Ablative Radiotherapy’, which is licensed to Natsar Pharmaceuticals, from which he receives royalties; reports consulting fees from RefleXion Medical Inc., Natsar Pharmaceuticals, Bayer Healthcare, Lantheus, Regeneron, AstraZeneca, Pfizer, Novartis, and J&J; reports meeting and/or travel support from RefleXion Medical, Bayer Healthcare, Janssen, and Lantheus, and holds leadership or fiduciary roles with NRG Oncology, ASTRO, and AACR. P.A.S. reports funding from the Prostate Cancer Foundation. The authors have no other 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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