Oligometastatic disease (OMD) is defined as an intermediate stage of cancer spread between locoregional and widespread metastatic disease and can include a wide spectrum of disease biologies and clinical behaviors (1). OMD is increasingly diagnosed in prostate cancer (PCa) owing on the one hand to improved detection with advanced imaging like prostate-specific membrane antigen (PSMA) PET-CT and on the other hand to the success of systemic therapies in prolonging cancer survival. Even so, the biological features of OMD are poorly defined. Until biomarkers are identified to distinguish OMDs with truly limited metastatic capacity from those with fast-progressing behavior, it is a reasonable strategy to select patients based on clinical assumptions. The European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) have proposed a classification in nine OMD subtypes, reflecting the different clinical states and underlying biological processes of OMD (2).

There is increasing evidence to suggest that patients with prostate OMD could benefit from more aggressive local treatment of the metastases, so-called metastasis-directed treatment, to obtain deep remission or possibly cure while preserving functional status (3, 4). In this regard, stereotactic ablative radiotherapy (SABR) offers a safe and effective treatment option.

Considering the lack of a standardized definition of oligometastatic disease, patient selection for SABR needs to be clarified. Therefore, the primary aim of this analysis was to report survival outcomes of a heterogeneous group of patients from a real-world setting with hormone-sensitive (HSPC) and castrate-resistant (CRPC) oligometastatic prostate cancer treated with SABR and analyze pattern of relapse.

In this article, we describe a single-institution experience treating PCa OMD with SABR at a median follow-up of 41.6 months. Our cohort consisted of 87 patients, a mixture of metachronous as well as synchronous OMD, HSPC as well as CRPC, oligorecurrent as well as oligoprogressive mPCa. In total, 41% of patients remained free from new metastases for a period of >18 months, and 25% of patients developed limited new metastases potentially amenable for repeat MDT within the first 18 months following SABR.

As a subgroup analysis, PSA response, bPFS and DMFS in (metachronous as well as repeat) oligorecurrent HSPC was evaluated. Two phase II RCT’s compared SABR to surveillance in the setting of metachronous oligorecurrent HSPC detected on choline PET-CT (3) or conventional CT and bone scintigraphy (4, 10), showing an advantage for MDT in terms of ADT-free survival and PFS. Despite 77% of our patients having PSMA PET-selected OMD, a more sensitive selection method than conventional CT, bone scintigraphy or choline PET-CT (11), our data do not compare as favorable as those reported in the aforementioned trials. It is remarkable that in our analysis, a PSA decline was measured in only 45% of patients receiving SABR without additional systemic treatment, as opposed to 75% in STOMP; median bPFS was 6 months in our cohort as opposed to >24 months in ORIOLE. These observations are probably related to several reasons, such as different bPFS definitions or the inclusion of 8 repeat oligorecurrent HSPC’s in our cohort.

However, it seems that still some cases were labelled as OMD if in fact it was only the tip of the iceberg for a subclinical polymetastatic disease. Therefore, we evaluated the impact of adding short-term ADT to SABR, to see if it is possible to eliminate potential micrometastases that are not (yet) visible and enhance the therapeutic effect. In our cohort, the addition of ADT for oligorecurrent HSPC was associated with improved bPFS (median 6.0 vs. 18.3 months, HR 0.31, p<0.001) and DMFS (median 15.8 vs 29.6 months, HR 0.5, p=0.06). While this analysis is exploratory and only hypothesis-generating, several phase II-III trials are currently testing the combination of SABR with either short course ADT (12–14) or androgen receptor pathway inhibitors (15). The main goal of this approach remains to postpone the start of lifelong ADT. Adding temporary hormonal treatment has already demonstrated improved LC, OS and MFS in primary treatment of high risk PCa (10).

New biomarkers may be critically important to help determining the natural history of the disease and to select the patients who could actually benefit from MDT. As of now, treatment decisions for OMD are based on clinical parameters such as number of metastases, time to recurrence and PSA doubling time. In a study by Deek et al., the presence of high-risk mutations was an independent prognostic factor allowing identification of patients who need more aggressive approaches beyond metastases-directed therapy (16). This suggests that tumor mutational profiles can provide a biological definition of OMD and complement currently used numerical definitions. Strategies for improved candidate selection have already been incorporated in prospective trials to provide a deeper understanding of the predictive role of biomarkers (12–14).

Looking at the oligo-CRPC patients of our analysis, DMFS and OS were significantly shorter compared to the HSPC patients, owing to the more advanced disease stage. Despite the more aggressive setting, median DMFS was still 17.6 months. During this time interval, it was not necessary to switch to a next line of systemic therapy. Moreover, in-field control was excellent, confirming the radiosensitivity of CRPC and the high efficacy of SABR on local metastatic control. While retrospective analyses testing the addition of SABR report encouraging results with DMFS ranging between 11 – 12 months (17–19), prospective data on the use of SABR in oligometastatic CRPC remain scarce, and several questions remain to be answered. For example, should we rather add SABR to the mainline systemic treatment to postpone next systemic treatment, or radically treat the visible metastases using SABR in combination with a switch to a next type of systemic treatment to target macroscopic as well as microscopic treatment-resistant disease? Regarding outcomes, is PFS a meaningful endpoint, or should we enroll larger patient groups and maintain long follow-up periods to evaluate OS endpoints? These questions warrant further exploration in prospective trials using standardized treatments to validate the potential benefit and to define the group of CRPC patients expected to profit from SABR. Ongoing prospective trials, such as the single-arm phase II TRAP trial (20) and the Medcare trial (21), are investigating the role of SABR for oligometastatic CRPC. Since immune-checkpoint inhibitor monotherapy has shown only modest benefits in the mCRPC setting, the ICE-PAC trial aimed at improving outcomes by combining the PD-L1 checkpoint inhibitor avelumab with SABR in patients with both low- as well as high-volume mCRPC after prior androgen-receptor pathway inhibitor therapy (22). A median radiographic PFS of 8.4 months was observed in this heavily pretreated patient group, of which the majority had >10 metastases.

The present study was limited by its retrospective nature, by the relatively small patient group and by the rather heterogeneous patient, imaging and tumor characteristics. The current cohort reflects a real-world representation of the imaging evolution in recurrent prostate cancer. Initially, conventional imaging was supplemented with whole body MRI before the advent of choline PET-CT and PSMA PET-CT improved the detection of oligometastatic disease. The results might have been even better when patients received the most sensitive imaging at restaging, as was also shown in ORIOLE where PFS and DMFS was improved when all PSMA-PET positive lesions were treated with SABR (4).

In this cohort, patients with hormone-sensitive oligometastatic disease showed potential benefit from SABR with a median distant metastasis-free survival of 22 months. Well-selected patients with oligometastatic CRPC may also benefit from SABR. For patients with metachronous and repeat oligorecurrent HSPC, combining SABR with short-term androgen-deprivation therapy was associated with improved bPFS and DMFS. Overall, 36/87 (41%) of patients were still free from clinical relapse at 18 months.

The data that support the findings of this study are available upon request from the corresponding author, CM, carole.mercier@gza.be. The data are not publicly available due to their containing information that could compromise the privacy of patients.

The studies involving human participants were reviewed and approved by Commissie Medische Ethiek GZA Ziekenhuizen, Oosterveldlaan 22, 2610 Wilrijk. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

CM had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: CM, PD, and PO. Acquisition of data: CM and PD. Analysis and interpretation of data: CM, PD, and PO. Drafting of the manuscript: CM, MC, BT, TD, KF, HV, PO, and PD. Critical revision of the manuscript for important intellectual content: CM, MC, BT, TD, KF, HV, PO, and PD. Statistical analysis: CM, PD, and PO. Supervision: CM, PD, and PO. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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