The 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting featured discussions on integrating radiotherapy innovations into contemporary practice for genitourinary cancers, particularly prostate cancer. Dr. Phuoc Tran presented insights on the 'space-time continuum' in metastatic castration-sensitive prostate cancer (mCSPC), emphasizing that space and time are clinical manifestations of underlying metastatic biology.
The Space-Time Continuum in mCSPC
Historically, a 'cure line' separated patients with localized, curable disease from those with incurable metastatic disease. However, the concept of oligometastatic disease has shifted this line, potentially including patients with limited metastases. The oligometastatic hypothesis, introduced by S. Hellman and R. R. Weichselbaum, posits an intermediate state between localized and widespread metastases that can be impacted by local therapies. Metastasis is viewed as a clonal process, where patients can undergo oligoclonal progression from an oligometastatic to a polymetastatic state.
The self-seeding and clonal progression hypothesis suggests that metastatic cells can cycle back to the primary tumor or seed new metastases. Ablating both primary and metastatic lesions may be necessary to alter the natural history of oligometastatic disease. The sub-consolidative hypothesis proposes that consolidative local therapies can alter the natural history if oligoprogression is a pathway to widely metastatic disease.
Impact of Metastatic Volume (Space)
Data from the STAMPEDE Arm H trial indicates that the volume of metastatic disease significantly impacts outcomes. Patients with CHAARTED low-volume disease experienced a significant overall survival benefit from adding prostate radiotherapy to systemic therapy (3-year overall survival: 65% vs. 53%, p<0.01). However, those with high-volume disease did not see a significant survival benefit (p=0.16). Additional data from STAMPEDE Arm H showed that the benefit of prostate radiotherapy decreases as the number of metastatic lesions increases, with radiotherapy best reserved for patients with ≤5 lesions.
Genomic correlates also appear to exist with the volume of metastatic disease. A 2023 retrospective review by Sutera et al. of patients with biochemically recurrent or mCSPC found that the frequency of driver mutations in WNT, cell cycle, TP53, and PI3K/AKT/mTOR pathways differed significantly between biochemically recurrent, low-, and high-volume disease, with a higher incidence of mutations in patients with higher metastatic volumes.
Consolidative Therapies and Clinical Trials
The total consolidative hypothesis involves combining metastasis-directed therapy (MDT) with systemic therapy in oligometastatic disease. The TERPs trial (NCT05223803), a phase II trial, is randomizing patients with de novo oligometastatic disease (<3 lesions on conventional imaging or <5 on PET/CT) to best systemic therapy plus primary prostate radiotherapy with or without MDT (SBRT). The primary endpoint is two-year failure-free survival.
For patients with de novo oligometastatic CSPC, level 1 data from STAMPEDE and PEACE-1 support local treatment intensification with external beam radiotherapy for the primary tumor. However, evidence for combining MDT (SBRT) to metastatic lesions with systemic therapy remains limited, with ongoing phase II single-arm studies.
Impact of Metastatic Timing (Time)
Dr. Tran highlighted that oligometastatic patients may present with either de novo (synchronous) or recurrent (metachronous) disease. Patients with synchronous metastases have significantly worse overall survival outcomes (5-year overall survival: 39% vs. 79%, p<0.01).
The timing of disease presentation correlates with underlying androgen receptor (AR) transcriptomics. Synchronous metastatic disease exhibits significantly lower median AR activity (11.8 vs. 12.6; p< 0.01) and hallmark androgen response (3.2 vs. 3.3; p<0.01) compared to metachronous disease. Synchronous disease patients are also more likely to have low AR activity (38% vs. 20%; p< 0.01) and low hallmark androgen response (58% vs. 38%; p< 0.01).
Evidence for MDT in Oligorecurrent mCSPC
Three key phase II trials—STOMP, ORIOLE, and SABR-COMET—have investigated MDT in this setting. STOMP, a multicenter, randomized phase II trial, evaluated MDT for eugonadal men with oligometastatic disease on choline PET/CT (≤3 extracranial sites) who had prior curative treatment and biochemical recurrence. After a median follow-up of 5.3 years, the five-year ADT-free survival was 8% in the surveillance arm versus 34% for the MDT group (HR: 0.57, 95% CI: 0.38–0.84, log-rank p=0.06).
The ORIOLE trial, a randomized phase II trial of 54 men with oligorecurrent mCSPC (≤3 sites), showed that disease progression at six months occurred in 19% of patients in the SBRT arm versus 61% in the observation arm (p=0.005). Patients in the SBRT arm had superior median progression-free survival (median: not reached vs. 5.8 months; HR: 0.30; 95% CI: 0.11–0.81; p=0.002). No grade ≥3 treatment-related adverse events were observed with SBRT.
SABR-COMET, a randomized, open-label phase II study of patients with oligometastatic disease (≤5 sites), included 18 prostate cancer patients. At a median follow-up of 5.7 years, overall survival was superior for SBRT-treated patients. The 8-year overall survival rates were 27% and 14% in the intervention and control arms, respectively (HR: 0.50, 95% CI: 0.30–0.84, p=0.008). The 8-year progression-free survival rates were 21% and 0%, respectively (HR: 0.45, 95% CI: 0.28–0.72, p<0.001).
The rates of grade ≥2 acute or late toxic effects were 30% versus 9% (p=0.019), with no new grade 3 to 5 toxic effects. Quality-of-life scores declined over time in both arms, but there were no differences between the study arms.
Key Take-Home Messages
Dr. Tran concluded that space and time in mCSPC are clinical manifestations correlated with outcome and can direct treatment. Understanding the underlying metastatic biology can inform the rational design of combination systemic and local therapy for metastatic disease. A better understanding of oligometastatic biology will have implications for polymetastatic disease.
