Why this matters
PSMA PET is increasingly identifying patients with very low-volume metastatic prostate cancer that remains invisible on conventional imaging.
That creates a management problem. These patients are technically metastatic, but their disease burden may consist of only one to three PSMA-avid lesions. Whether they should receive continuous systemic therapy, intermittent ADT, metastasis-directed treatment, or some combination remains uncertain.
The randomized i-STOP study tested a clinically attractive strategy: use SBRT to eradicate all PSMA PET-defined metastatic deposits while maintaining an intermittent rather than continuous ADT approach.
The strongest efficacy signal was a substantial reduction in biochemical progression.
Study design
i-STOP was a prospective randomized study enrolling patients with hormone-sensitive oligometastatic prostate cancer detected by PSMA PET.
Patients had:
- up to 3 PSMA-avid metastatic sites
- negative conventional staging
- synchronous or metachronous metastatic disease
Patients were randomized to:
- intermittent ADT alone
- intermittent ADT plus SBRT to all metastatic deposits
For patients with synchronous disease, prostate-directed radiotherapy was also delivered in the experimental arm.
Intermittent ADT was administered in 8-month cycles.
After the initial 8 months, ADT could be restarted when:
- PSA exceeded 10 ng/mL
- new metastatic disease developed
- the treating physician considered earlier treatment necessary
The primary endpoint was feasibility of randomization.
Key secondary endpoints included:
- biochemical progression
- PSA nadir
- time to re-initiation of ADT
Sixty patients were enrolled:
- 29 received intermittent ADT alone
- 31 received intermittent ADT plus SBRT
Almost all patients, 97%, had metachronous disease.
Median follow-up was 36 months.
Key results
The randomized study successfully demonstrated feasibility, with 60 of 66 eligible patients enrolling.
The most important clinical result was biochemical progression.
At 3 years, cumulative biochemical progression was:
- 60% with intermittent ADT alone
- 21% with intermittent ADT plus SBRT
- p=0.004
Median time to biochemical progression was:
- 27.3 months with intermittent ADT alone
- not reached with intermittent ADT plus SBRT
PSA nadir itself was similar between groups.
Median PSA nadir was approximately:
- 0.02 ng/mL in both arms
The proportions reaching PSA below 0.2 ng/mL or below 0.02 ng/mL were also not significantly different.
ADT re-initiation
At 3 years, ADT had been restarted in:
- 41% with intermittent ADT alone
- 18% with intermittent ADT plus SBRT
The difference did not reach conventional statistical significance:
- p=0.06
Median time to ADT re-initiation was:
- 36.4 months with intermittent ADT alone
- not reached with intermittent ADT plus SBRT
The direction of effect therefore favors metastasis-directed SBRT, but the current data do not establish a statistically significant reduction in ADT re-initiation.
Interpretation
The most convincing message from i-STOP is that treating all PSMA PET-defined metastatic lesions with SBRT substantially delayed biochemical progression during an intermittent ADT strategy.
The absolute difference at 3 years is large: 60% biochemical progression with intermittent ADT alone compared with 21% when SBRT was added.
That supports the biological premise of metastasis-directed therapy in molecularly detected oligometastatic disease.
The study is also interesting because it addresses a population that increasingly appears in routine practice but remains poorly represented in older randomized trials: patients who are metastatic by PSMA PET but negative on conventional staging.
The ADT re-initiation result is encouraging but should be framed more cautiously. A reduction from 41% to 18% is clinically meaningful numerically, but p=0.06 means the trial did not demonstrate a statistically significant difference for that endpoint.
There is another important limitation to the strength of the efficacy conclusion.
The primary endpoint of i-STOP was feasibility of randomization, not biochemical progression. The disease-control endpoints were secondary, and only 60 patients were randomized.
This makes the biochemical progression result compelling, but not definitive enough to establish a new standard of care.
The study also does not tell us whether SBRT improves metastasis-free survival, castration-resistant progression, or overall survival.
Limitations
The study was small, with only 60 randomized patients.
The primary endpoint was feasibility rather than oncologic efficacy.
Biochemical progression and ADT re-initiation were secondary endpoints.
The ADT re-initiation difference did not reach statistical significance.
Almost all patients had metachronous disease, so the findings provide limited evidence for synchronous PSMA PET-only oligometastatic disease.
The study also compared intermittent ADT strategies rather than contemporary continuous systemic intensification, limiting direct comparison with current treatment approaches for metastatic hormone-sensitive prostate cancer.
Longer follow-up is needed to determine whether delaying biochemical progression translates into improvements in clinically harder endpoints.