Highlights
- The PORTAL study establishes an international, validated nomogram to predict androgen deprivation therapy (ADT)-free survival in men with PSMA PET-detected oligorecurrent prostate cancer.
- Key independent predictors of earlier ADT initiation include higher pre-treatment PSA, shorter PSA doubling time (PSADT), a higher number of lesions (3–5), and the presence of distant versus nodal-only metastases.
- While individual-level discrimination was modest (C-index 0.65–0.66), the tool successfully stratified patients into three distinct prognostic groups, facilitating more personalized Metastasis-Directed Therapy (MDT) decisions.
- MDT using SBRT achieved a 1-year ADT-free survival rate exceeding 84%, reinforcing its role in delaying systemic therapy and its associated side effects.
Background
The management of metachronous oligorecurrent hormone-sensitive prostate cancer (mHSPC) has been fundamentally transformed by the advent of molecular imaging, specifically Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET). This technology allows for the detection of low-volume metastatic disease at much lower PSA levels than conventional imaging, leading to the clinical emergence of the “oligometastatic” state—typically defined as five or fewer detectable lesions. In this context, Metastasis-Directed Therapy (MDT), primarily delivered via Stereotactic Body Radiotherapy (SBRT), has gained traction as a strategy to eradicate visible disease and potentially delay the initiation of Androgen Deprivation Therapy (ADT).
The primary clinical goal of MDT in these patients is to extend the ADT-free survival (AFS) interval, thereby preserving quality of life and avoiding the metabolic, cardiovascular, and psychological side effects associated with testosterone suppression. However, patient responses to MDT are highly heterogeneous. While some patients experience durable remissions lasting years, others progress rapidly to polymetastatic disease. Historically, clinicians lacked robust, validated tools to identify which patients are most likely to benefit from SBRT alone and which require early systemic intensification. The PORTAL study (Nomogram-based risk classification for predicting response to metastasis-directed stereotactic body radiotherapy in PSMA PET-staged oligorecurrent prostate cancer) was designed to fill this critical gap in evidence-based risk stratification.
Key Content
Evolution of Evidence for MDT in Oligorecurrent Disease
The clinical rationale for MDT is supported by several landmark trials. The STOMP trial (Journal of Clinical Oncology, 2018) was among the first to show that MDT improved ADT-free survival compared to surveillance in oligometastatic prostate cancer. This was followed by the ORIOLE trial (JAMA Oncology, 2020), which demonstrated that SBRT reduced the risk of progression and that the benefit was particularly pronounced when all PSMA-avid lesions were treated. Despite these successes, these earlier trials were often limited by small sample sizes and varying definitions of oligometastatic disease.
The PORTAL study represents a significant advancement by providing a large-scale, international retrospective cohort (n=1,461 screened, n=717 included in final cohorts) specifically staged with PSMA PET. By utilizing data from ten academic centers across Europe, the study offers real-world evidence of how clinical variables influence MDT outcomes in a modern imaging landscape.
The PORTAL Study: Methodology and Model Development
The development cohort consisted of 586 patients from centers in Austria, Italy, Latvia, the Netherlands, Poland, and Portugal. Eligibility criteria were stringent: histologically confirmed prostate cancer, previous curative-intent local therapy, metachronous oligoreoccurrence (≤5 lesions on PSMA PET), and treatment with SBRT to all lesions without concurrent systemic therapy. The primary endpoint was the proportion of patients remaining ADT-free at one year.
The researchers evaluated ten clinical predictors, eventually narrowing them down via a multivariable Cox model. The final nomogram identified four critical variables that independently predicted the risk of starting ADT:
- Pre-MDT PSA levels: Higher levels correlated with a higher hazard of ADT initiation (HR 1.05).
- PSA Doubling Time (PSADT): A shorter doubling time, reflecting more aggressive tumor biology, was a significant predictor of failure (HR 0.97).
- Number of Lesions: Patients with 3–5 lesions had a 74% higher risk of progression compared to those with 1–2 lesions (HR 1.74).
- Location of Metastases: Distant metastases (bone or visceral) carried a worse prognosis than pelvic nodal-only disease (HR 1.45).
Validated Results and Risk Stratification
The external validation cohort (n=131) confirmed the model’s utility. The 1-year ADT-free survival was remarkably high at 84.3% in the development cohort and 92.8% in the validation cohort. Although the C-index (a measure of individual predictive accuracy) was modest at 0.65–0.66, the model excelled at group-level stratification. By dividing patients into low-risk, intermediate-risk, and high-risk categories, the researchers demonstrated statistically significant (p<0.0001) differences in long-term ADT-free survival. This suggests that while the nomogram might not predict the exact month a patient will require ADT, it is highly effective at identifying the broad trajectory of the disease.
Mechanistic Insights into PSA Kinetics and Tumor Burden
The inclusion of PSA doubling time and lesion count in the nomogram reflects the biological underpinnings of prostate cancer progression. A short PSADT is a surrogate for rapid cellular proliferation and a high likelihood of subclinical micro-metastatic disease that current PET scans cannot yet resolve. Similarly, the transition from 1–2 lesions to 3–5 lesions may represent a biological tipping point where the tumor’s metastatic efficiency increases. These findings align with the “seed and soil” hypothesis, where the burden of systemic disease is a reflection of both the aggressiveness of the primary clone and the receptivity of distant metastatic niches.
Expert Commentary
Clinical Applicability and Guidelines
The PORTAL nomogram provides a much-needed objective framework for the multidisciplinary tumor board. Current EAU and NCCN guidelines acknowledge MDT as an option but offer little guidance on patient selection. With this tool, clinicians can now offer more nuanced counseling. For a “low-risk” patient (e.g., a single pelvic node, long PSADT, low PSA), the confidence in recommending SBRT to defer ADT is high. Conversely, for a “high-risk” patient (e.g., 4 bone lesions, rapid PSADT), the nomogram suggests that SBRT alone is unlikely to provide a long ADT-free interval, perhaps indicating a need for combined MDT and systemic therapy (intensification).
Limitations and Controversies
The retrospective nature of the study is an inherent limitation, introducing potential selection bias regarding which patients were offered MDT versus primary ADT. Furthermore, the definition of “initiation of ADT” can be subjective and varies by institutional practice, which may explain why the C-index was not higher. There is also the ongoing debate regarding the “PSMA-PET stage migration” (the Will Rogers phenomenon), where more sensitive imaging discovers more disease, potentially making outcomes appear better than they were in the era of conventional CT/Bone scans.
Integrating Molecular Biomarkers
Future iterations of this risk classification system should aim to incorporate molecular biomarkers, such as circulating tumor DNA (ctDNA) or genomic classifiers (e.g., Decipher). As shown in subset analyses of the ORIOLE trial, patients with high-risk genomic signatures derive less benefit from MDT alone. Combining the clinical variables of the PORTAL nomogram with genomic insights could push individual-level discrimination (C-index) toward the 0.75–0.80 range.
Conclusion
The PORTAL study provides a robust, internationally validated tool for risk-stratifying patients with PSMA PET-staged oligorecurrent prostate cancer. By integrating PSA kinetics and lesion characteristics, the nomogram allows clinicians to move beyond a “one-size-fits-all” approach to metastasis-directed therapy. While MDT remains an effective tool for delaying ADT in the majority of patients, the identification of low, intermediate, and high-risk cohorts is a vital step toward precision oncology in mHSPC. Future research must now focus on whether high-risk patients identified by this nomogram benefit from the early addition of novel hormone agents (e.g., abiraterone, enzalutamide) alongside SBRT.
References
- Soeterik TFW, et al. Nomogram-based risk classification for predicting response to metastasis-directed stereotactic body radiotherapy in PSMA PET-staged oligorecurrent prostate cancer (PORTAL): an international, retrospective cohort study. Lancet Oncol. 2026;27(3):S1470-2045. PMID: 41713474.
- Ost P, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Case-Control Study (STOMP). J Clin Oncol. 2018;36(5):446-453. PMID: 29215951.
- Phillips R, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-659. PMID: 32215598.
- Palma DA, et al. Stereotactic ablative radiotherapy versus standard of care treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058. PMID: 30982687.
