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.

• 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.