PSMA PET-Staged Comprehensive Progression-Directed Radiotherapy for Limited Progression in Prostate Cancer

PSMA-OLIGO-PRO is a multicenter, ambispective, observational real-world evidence registry of adults with metastatic prostate adenocarcinoma who develop limited progression during active systemic therapy and are considered for comprehensive progression-directed radiotherapy (PDRT) in routine clinical practice. The study does not assign imaging, systemic therapy, or radiotherapy. Decisions to obtain PSMA PET, to determine the pre-PDRT systemic-management plan, and to consider comprehensive PDRT are made independently of registry participation. The registry comprises three calendar-defined data-origin cohorts: (1) a retrospective classical-burden cohort treated before June 26, 2026, with 1-5 qualifying progressing metastatic lesions; (2) a prospective pre-amendment classical-burden cohort enrolled from June 26, 2026, until the amendment becomes effective at each site, with 1-5 qualifying progressing metastatic lesions; and (3) a post-amendment prospective cohort with 1-10 qualifying progressing metastatic lesions. Within the post-amendment cohort, burden is prespecified as 1-5 versus 6-10 metastatic lesions. Six to ten lesions constitute an exploratory expanded-burden limited-progression stratum and are not presented as an established consensus definition of oligoprogression. Baseline PSMA PET/CT or PSMA PET/MRI is mandatory for every included episode. For post-amendment prospective enrollment, the qualifying PSMA PET must be performed within 60 days before enrollment, and index PDRT must be planned to begin within 60 days after the scan. Repeat staging or documented multidisciplinary reconfirmation is required if this interval is exceeded or if an intervening clinical event or systemic-treatment change could alter metastatic burden. The eligibility ceiling and burden stratum are based only on qualifying progressing metastatic lesions. Intraprostatic and prostate-bed progressing foci are recorded separately, do not count toward the metastatic ceiling, and must also be included in the comprehensive PDRT plan. Otherwise eligible patients with zero progressing metastases and isolated local or prostate-bed progression form a separate descriptive stratum and do not contribute to the metastatic-burden comparison or metastatic-threshold progression endpoints. Before prospective analytic-cohort enrollment, all qualifying metastatic and local progressing sites must be judged technically amenable to definitive-intent PDRT. Candidates deemed feasible are enrolled before the first PDRT fraction. Prospectively enrolled participants who do not start or do not complete all planned PDRT remain in the enrolled and implementation denominators. Only participants receiving at least one PDRT fraction enter the prospective safety set and the treatment-start clinical-outcome sets. PDRT may include stereotactic body radiotherapy, moderately hypofractionated external-beam radiotherapy, high-dose-rate or low-dose-rate brachytherapy, combined external-beam and brachytherapy, or mixed-modality treatment, according to institutional standards. Every qualifying metastatic and local progressing site must be included in a predefined index treatment strategy. For post-amendment prospective participants, PDRT initiation is assessed within 60 days after enrollment, and comprehensive implementation requires definitive-intent treatment of every locked baseline site within 60 days after the first index fraction. The primary endpoint is time to next systemic therapy (TTNS) in treatment-start participants whose pre-PDRT management plan was continuation of the same systemic regimen and who had not initiated a new systemic therapy line before the first PDRT fraction. Participants with a documented pre-PDRT plan to change or escalate systemic therapy are excluded from the primary TTNS estimand but remain eligible for other analyses. The broad TTNS definition used in the first posted registry version is retained as a supportive analysis for all treatment-start participants. The common expanded-state progression endpoint is time to widespread or non-PDRT-amenable progression (TWNP-10), defined by more than 10 new or unequivocally regrowing metastatic lesions, diffuse or non-enumerable progression, or a documented determination that all active progressing sites can no longer be safely treated with comprehensive definitive-intent local therapy. A supportive classical endpoint, TTPP-5, is restricted to participants with 1-5 metastatic lesions at baseline and retains the threshold of more than five progressing metastatic lesions or loss of comprehensive PDRT eligibility. Other outcomes include radiographic progression-free survival, lesion-level local control, overall survival, repeat limited progression, subsequent lesion-directed therapy, PDRT initiation and comprehensive implementation, disease trajectory, and acute and late treatment-related adverse events graded according to CTCAE version 5.0. The primary 1-5 versus 6-10 metastatic-burden comparison is limited to concurrent post-amendment prospective participants and uses endpoint-specific denominators. All comparisons are exploratory and estimate associations rather than causal treatment effects.

The coordinating center uses a controlled data dictionary and prespecified edit checks for date order, metastatic-count consistency, cohort assignment, lesion-to-treatment linkage, dose and fraction plausibility, endpoint derivation, and duplicate records. Data queries are sent to participating sites for correction or documented resolution. Selected post-amendment records, enriched for 6-10 metastases and discordant disease, may undergo source-data, imaging, and treatment-completeness review. Missingness is reported by data-origin cohort and burden stratum, and time-to-event observations without an event are censored at the last adequate assessment. The statistical analysis plan will be finalized before the comparative post-amendment data lock.

• Comprehensive Progression-Directed Radiotherapy (Radiation), also known as PDRT, Stereotactic Body Radiotherapy, SBRT, Brachytherapy, Metastasis-Directed Therapy, MDT: Observed routine-care exposure includes definitive-intent radiotherapy planned for every qualifying metastatic site and for local or prostate-bed progressing sites identified in the index episode. Treatment may include stereotactic body radiotherapy, moderately hypofractionated external-beam radiotherapy, high-dose-rate or low-dose-rate brachytherapy, combined external-beam and brachytherapy, or mixed-modality radiotherapy. The registry does not assign treatment. Treatment modality, dose, fractionation, timing, site-level completion, and reasons for non-start or incomplete treatment are recorded.

Primary outcomes

• Time to Next Systemic Therapy in the Continuation-Plan Treatment-Start Set [From first index PDRT fraction to a new systemic therapy line, death, last adequate assessment, or study data cutoff, up to 5 years]: Time from the first PDRT fraction to initiation of the first new systemic anticancer therapy line among participants who receive at least one PDRT fraction, whose management plan documented before PDRT was continuation of the same systemic regimen, and who had not initiated a new systemic line before the first PDRT fraction. Death before initiation of a new line is treated as a competing event; otherwise, participants are censored at the last adequate assessment.

Secondary outcomes

• Classical Time to Polymetastatic Progression (TTPP-5) [From first index PDRT fraction to the event, death, last adequate assessment, or study data cutoff, up to 5 years]: Supportive endpoint restricted to participants with 1-5 qualifying progressing metastases at baseline. Time to more than five new or unequivocally regrowing qualifying metastatic lesions at one assessment or to disease that is no longer safely amenable to comprehensive PDRT. Participants entering with 6-10 metastases do not contribute. Death without the progression state is treated as a competing event.
• Radiographic Progression-Free Survival [From first index PDRT fraction to radiographic progression, death, last adequate assessment, or study data cutoff, up to 5 years]: Time from the first index PDRT fraction to radiographic progression at any site or death from any cause, whichever occurs first. Imaging modality and assessment date are recorded. Progression based only on an unconfirmed change in PSMA uptake is not accepted unless it meets the protocol confirmation criteria.
• Overall Survival [From first index PDRT fraction to death, last known follow-up, or study data cutoff, up to 5 years]: Time from the first index PDRT fraction to death from any cause. Participants alive at the last known follow-up are censored on that date.
• Lesion-Level Local Control [From completion of PDRT for each lesion to local failure, death, last adequate assessment, or study data cutoff, up to 5 years]: Time from completion of PDRT for an individual treated lesion to unequivocal in-field progression of that lesion. Lesions are linked to participants and analyzed with methods that account for within-participant clustering. Death without local failure is treated as a competing event.
• Acute and Late Treatment-Related Adverse Events [From first index PDRT fraction through day 90 for acute events and from day 91 through study data cutoff, up to 5 years, for late events]: Number and proportion of prospectively enrolled participants who receive at least one index PDRT fraction and experience treatment-related adverse events graded by CTCAE version 5.0. Acute events occur through day 90 after treatment initiation and late events occur after day 90. Maximum grade, serious events, grade 2 or higher events, grade 3 or higher events, and selected site-specific toxicities are summarized. Retrospectively ascertained toxicity is reported separately when adequate.
• Time to First Repeat Limited-Progression Episode [From first index PDRT fraction to repeat limited progression, death, last adequate assessment, or study data cutoff, up to 5 years]: Time from the first index PDRT fraction to the first subsequent limited-progression episode with no more than 10 new or unequivocally regrowing qualifying metastatic lesions at one assessment and with every active progressing metastatic and local site judged technically amenable to comprehensive PDRT. Death before repeat limited progression is treated as a competing event; otherwise participants are censored at the last adequate assessment.
• Time to Next Systemic Therapy in All Treatment-Start Participants [From first index PDRT fraction to a new systemic therapy line, death, last adequate assessment, or study data cutoff, up to 5 years]: Supportive analysis of time from the first fraction of index PDRT to initiation of the first new systemic anticancer therapy line among all participants who receive at least one PDRT fraction, regardless of the pre-PDRT intended systemic-management strategy. This outcome preserves the population scope of the first posted registry version. Death before a new line is treated as a competing event; otherwise participants are censored at the last adequate assessment.
• Time to Widespread or Non-PDRT-Amenable Progression (TWNP-10) [From first index PDRT fraction to the event, death, last adequate assessment, or study data cutoff, up to 5 years]: Time to the earliest of more than 10 new or unequivocally regrowing qualifying metastatic lesions at one assessment; diffuse, confluent, or otherwise non-enumerable progression; or a documented multidisciplinary determination that all active progressing sites can no longer be safely treated with comprehensive definitive-intent local therapy. Death without this progression state is treated as a competing event.
• Time to First Subsequent Lesion-Directed Therapy [From first index PDRT fraction to subsequent lesion-directed therapy, last adequate assessment, or study data cutoff, up to 5 years]: Time from the first index PDRT fraction to initiation of the first subsequent local treatment course for repeat limited progression. Participants without subsequent lesion-directed therapy are censored at the last adequate assessment.

Other outcomes

• Disease Trajectory After Index PDRT [From first index PDRT fraction to the first qualifying trajectory state, death, or study data cutoff, up to 5 years]: Number and proportion of participants whose first post-PDRT trajectory is repeat limited progression involving no more than 10 qualifying progressing metastases, crossing of the classical threshold of more than five progressing metastases, direct widespread or non-PDRT-amenable progression, or death without documented progression.

Sex: Male, ages: 18 Years to any

* Age 18 years or older.
* Histologically confirmed prostate adenocarcinoma.
* Metastatic hormone-sensitive or metastatic castration-resistant prostate cancer.
* Active systemic anticancer therapy at the qualifying limited-progression assessment.
* Qualifying baseline PSMA PET/CT or PSMA PET/MRI with review of relevant anatomical imaging.
* Metachronous, repeat, or induced oligoprogression or limited progression according to the protocol framework.
* Retrospective cases treated before June 26, 2026: 1-5 qualifying progressing metastatic lesions.
* Prospective cases enrolled before the site-specific amendment effective date: 1-5 qualifying progressing metastatic lesions.
* Prospective cases enrolled after the site-specific amendment effective date: 1-10 qualifying progressing metastatic lesions, prespecified as 1-5 or 6-10.
* Intraprostatic or prostate-bed progressing foci are recorded separately from the metastatic-lesion count and must also be technically amenable to comprehensive PDRT.
* Every qualifying metastatic and local progressing site is judged technically amenable to comprehensive definitive-intent PDRT before prospective analytic-cohort enrollment.
* For post-amendment prospective enrollment, qualifying PSMA PET performed within 60 days before enrollment and index PDRT planned to begin within 60 days after the scan.
* Availability of the qualifying PET date, systemic-therapy dates, locked metastatic-lesion count, separate local-site count, lesion map, and eligibility decision. For retrospective inclusion, PDRT exposure and at least one outcome or censoring time must also be determinable.

Exclusion Criteria

* Limited progression defined only by conventional CT, MRI, or bone scintigraphy without a qualifying PSMA PET examination.
* More than five qualifying progressing metastatic lesions for retrospective or pre-amendment inclusion.
* More than 10 qualifying progressing metastatic lesions after amendment activation.
* Diffuse, non-enumerable, or rapidly progressive disease that is not considered suitable for comprehensive lesion-directed radiotherapy.
* Any known active metastatic or local progressing site that cannot be included in the comprehensive PDRT plan.
* Clinical deterioration or an urgent systemic-treatment indication that makes comprehensive PDRT inappropriate or unsafe.
* Radiotherapy delivered solely with palliative symptom-control intent rather than definitive progression-directed local-control intent.
* For prospective participation, inability to complete the approved consent process.
* For retrospective cases, missing baseline imaging or core dates such that metastatic burden, PDRT exposure, or at least one outcome or censoring time cannot be determined reliably.

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