<p>Several presentations at the recent <strong>2025 ASTRO Annual Meeting</strong> included updates on the biology of oligometastatic prostate cancer and the role of stereotactic body radiation therapy (SBRT) as metastasis-directed therapy (MDT).</p> <p><br></p> <p><em>Following these presentations, featured expert Amar U. Kishan, MD, was interviewed by </em>Conference Reporter<em> Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Kishan on these findings are presented here.</em></p>

There were a number of studies presented at ASTRO 2025 on the biology of oligometastatic disease and the role that MDT might play. A major highlight from the conference for me was that, in some oligometastatic disease settings, MDT appears to elicit an antitumor immune response that can be very helpful.

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For example, there was a late-breaking abstract on the phase 2 EXTEND trial (abstract LBA 11) that evaluated responses to MDT in different histology-specific “baskets” of oligometastatic disease (ie, prostate, pancreas, breast, kidney, and others). Results showed that the median progression-free survival was improved by adding MDT to the standard of care in both the prostate cancer and the pancreatic cancer baskets, but not in the breast cancer or kidney cancer baskets.

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Further, in the histologies for which MDT was beneficial, there was greater expansion and contraction of the T-cell receptor clones in association with the MDT. Conversely, in the histologies for which MDT was not beneficial, there was not that significant immune activation. Clearly, there are several different factors at play here, but this suggests to me that it might be possible to correlate the benefits of MDT with immune activation.

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Findings from EXTEND paralleled some of our own findings on immune stimulation from the LUNAR trial, which were also presented at ASTRO 2025 in abstract 3. LUNAR was a phase 2 trial of radioligand therapy neoadjuvant to ablative radiotherapy for oligorecurrent prostate cancer, and we conducted it to test the hypothesis that prostate-specific membrane antigen–targeted radioligand therapy followed by metastasis-directed SBRT can improve progression-free survival by acting on occult, microscopic disease. In the LUNAR trial, we saw that increased productive T-cell receptor rearrangements 90 days post SBRT were prognostic for the whole cohort overall. Moreover, there was a significant association between productive rearrangements at 90 days and a reduced hazard of progression.

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We are at the frontier of using disease biology to guide and optimize MDT, and there was an educational session at ASTRO 2025 that essentially outlined the different aspects of this frontier. It included presentations by Phuoc Tran, MD, PhD, Matthew Deek, MD, and Philip Sutera, MD. A major theme was the consolidative hypothesis; that is, if oligoprogressive clonal disease is a pathway to widely metastatic disease, then local consolidative therapy should alter the natural history. And we have actually already seen this in the STAMPEDE trial, in which consolidative radiotherapy to the primary tumor improved survival in a subset of patients with largely low-volume de novo disease.

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During his presentation from the educational session, Dr Tran highlighted some very compelling ongoing work, including the phase 2 randomized TERPS trial, which is looking at treating the primary tumor plus adding MDT (ie, the idea of a full consolidation of therapy). In general, other interesting presentations at ASTRO 2025 touched on not only the extent of disease (eg, oligometastatic vs polymetastatic) but also the timing characteristics of the onset of disease (ie, de novo vs metachronous or recurrent), which would be potentially driven by underlying biology.

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Ongoing work to identify a high-risk mutational signature in oligometastatic hormone-sensitive prostate cancer is one of the very interesting things that has been published previously, but this was emphasized during Dr Deek’s presentation at ASTRO 2025. In some analyses, it appears that MDT is even more beneficial in patients with high-risk mutations than in those without. This type of work led to the phase 2 KNIGHTS trial, which may be the first of its kind (ie, a molecularly stratified MDT trial in oligometastatic prostate cancer).

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In terms of future directions, I think that we have a number of key open questions. Who is going to benefit from systemic therapy intensification? Who is going to benefit from early vs late MDT? There are clearly both patient- and tumor-specific features that are important. Maybe we will see more biomarker work that really hammers this down at the next couple of ASTRO meetings, as well as at the next American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium and the ASCO Annual Meeting.