177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for 177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer (NCT03805594), a non-randomized phase 1 study. The primary outcome is Number of Reported Dose Limiting Toxicities (DLT) (Part A Only).

2. Clinical Question

3. Trial Design

This completed phase Ib study investigated lutetium Lu 177-PSMA-617 in combination with pembrolizumab in metastatic castration-resistant prostate cancer. The sponsor was the University of California, San Francisco. The registry lists a start date of 2019-05-10, primary completion on 2024-01-10, and an enrollment of 43.

The study was non-randomized, unmasked, and sequential. Part A evaluated three schedules. Schedule 1 gave a single priming dose of lutetium Lu 177-PSMA-617 28 days before pembrolizumab. Schedule 2 gave the priming dose concomitantly with pembrolizumab. Schedule 3 began maintenance pembrolizumab before giving the priming dose of lutetium Lu 177-PSMA-617. The registry describes pembrolizumab at 200 mg every 3 weeks for the Schedule 3 approach.

Part B used the recommended Phase 2 dosing schedule determined from Part A. The registry identifies Schedule 1, with lutetium Lu 177-PSMA-617 given 28 days before pembrolizumab, as the selected schedule. This sequence means that Part B did not provide a separately randomized comparator for Part A or for another treatment. Differences between the schedule groups cannot be interpreted as treatment effects from a randomized comparison.

The primary outcome was the number of reported dose-limiting toxicities in Part A, with a timeframe of up to 1 year. The registry also lists outcomes including treatment-related adverse events, duration of response, PSA response, radiographic progression-free survival, PSA progression-free survival, overall survival, and time to a symptomatic skeletal-related event. Numerical results for these outcomes are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: In Part A, three dosing schedules of priming lutetium-177 (¹⁷⁷Lu)-PSMA-617 (vipivotide tetraxetan) were assessed. Dose expansion in phase 1b (Part B) was subsequently evaluated using the recommended phase 2 dosing schedule.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Schedule 1, a single priming dose of 177Lu-PSMA-617 given 28 days before pembrolizumab was determined to be the RP2DS for participants enrolled under Part B

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Reported Dose Limiting Toxicities (DLT) (Part A Only), measured over Up to 1 year.

The primary endpoint is the number of reported dose-limiting toxicities in Part A, assessed over up to 1 year. The registry states that these toxicities were classified using NCI Common Terminology Criteria for Adverse Events version 5.0. The registry describes the endpoint as part of determining the recommended Phase 2 dosing schedule, alongside aggregate safety data and feasibility of administration.

A dose-limiting toxicity endpoint is used in early-phase studies to help assess whether a treatment schedule has safety concerns that constrain further study. In general, it focuses attention on specified toxicities during a defined assessment period, rather than estimating comparative efficacy. Its interpretation depends on the study’s toxicity definitions, assessment rules, and the number of participants evaluated. Those detailed rules and the numerical dose-limiting toxicity counts are not reported in the registry record.

The registry reports that Schedule 1 was selected as the recommended Phase 2 dosing schedule for Part B. That selection is a design decision informed by safety and feasibility, not a numerical estimate of comparative benefit. The record does not provide dose-limiting toxicity counts by Part A schedule, so the extent of the safety differences among schedules cannot be quantified from the reported information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design determines what the study can establish statistically. This was a non-randomized, sequential study with three schedules in Part A and a selected schedule in Part B. Participants were not randomly allocated among the schedules, and there was no independent randomized control group. The schedule groups can be described, but differences between them cannot be interpreted as unbiased treatment contrasts in the way a randomized comparison might be.

What does a dose-limiting toxicity count represent?

In general, a dose-limiting toxicity count records the number of participants who meet a prespecified toxicity definition during an assessment period. The endpoint is useful in early-phase research because it helps inform whether a regimen or schedule should be carried forward. The registry identifies NCI Common Terminology Criteria for Adverse Events version 5.0 as the classification system and gives the timeframe as up to 1 year. The specific toxicity rules, assessment population, and counting procedures are not reported in the registry record.

Counts should be read with their denominators. A count alone does not show the probability of toxicity unless the number of participants assessed is also known, and estimates based on small groups can be imprecise. The registry record identifies the enrollment and the arm sizes for the safety outcomes, but it does not provide the primary dose-limiting toxicity counts by schedule. It is therefore not possible to calculate or interpret schedule-specific primary endpoint rates from the posted information.

How should schedule selection be understood?

The registry states that the recommended Phase 2 dosing schedule was determined from Part A using safety data, aggregate safety data, and feasibility of administration. Schedule 1 was selected for Part B. In general, a selected schedule is the outcome of a decision process, not a direct statistical estimate of superiority. Without the underlying toxicity counts, decision thresholds, and comparative estimates, the record does not show how much the evidence favored one schedule over another or how uncertain that decision was.

Part B followed Part A and used the selected schedule. This sequential structure is useful for carrying a regimen forward, but it does not create a concurrent randomized control. Part B’s participants may differ from those in Part A, and treatment experience may also differ by study period. Accordingly, descriptive outcomes across Parts A and B should not be treated as randomized evidence that the chosen schedule caused better outcomes.

What do confidence intervals and p-values contribute?

In general, a confidence interval describes the range of effect estimates compatible with the observed data under the model and assumptions used. A narrow interval indicates greater precision than a wide interval, while an interval that includes values consistent with no difference may leave substantial uncertainty about the direction or size of an effect. A p-value measures how incompatible the observed data are with a specified null model; it does not measure the probability that a treatment works, nor does it quantify clinical importance.

The registry record does not report inferential analyses, p-values, confidence intervals, or model-based estimates for the listed clinical outcomes. No statistical conclusion about differences in efficacy or safety should therefore be inferred from the schedule selection or from descriptive adverse-event counts alone.

What do the planning illustrations mean?

General sample-size illustrations based on an observed effect are planning tools, not evidence that the study had a particular probability of detecting an effect. The stated assumptions use a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the target effect described as a fraction of the observed effect. For time-to-event outcomes, the illustration concerns total events; for other outcomes, it concerns participants per arm. These assumptions describe the illustrations, not the original trial design. They should not be described as observed power, and they do not supply missing outcome estimates or resolve the lack of randomization.

Over-dispersion is a general statistical concern when outcome variability is greater than a model assumes. If ignored, standard errors may be too small and confidence intervals too narrow. The registry record does not report a model or variance analysis for the listed outcomes, so there is no basis for saying whether over-dispersion was assessed or how it affected an analysis.

Overall, the design supports a descriptive account of schedule development and reported safety. The absence of numerical primary endpoint results and inferential estimates limits assessment of both effect size and precision. The non-randomized sequence further limits causal comparisons among the schedules.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple outcomes beyond the primary dose-limiting toxicity count. These include treatment-related adverse events, median duration of response, PSA response rate (PSA50), radiographic progression-free survival rate at 6 months, median PSA progression-free survival, median overall survival, and median time to symptomatic skeletal-related event. The registry also reports nine outcome measures in total. Numerical results for these outcomes are not reported in the registry record.

When a study examines multiple outcomes or makes several comparisons, the chance of obtaining at least one apparently notable result can increase. In general, multiplicity procedures may control error rates or distinguish primary from exploratory analyses. The registry record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or which outcomes were treated as confirmatory versus exploratory. No conclusions about such procedures should be assumed.

Missing-data methods and analysis populations are also not reported in the registry record. The record does not specify how participants who discontinued, had incomplete follow-up, or lacked an outcome assessment were handled. It also does not define analysis populations for the efficacy outcomes or explain whether participants were analyzed according to treatment received, enrollment group, or another rule. These details matter because different approaches can produce different estimates, particularly for response and time-to-event outcomes.

The registry identifies an enrollment of 43, but enrollment alone does not establish how many participants contributed to each outcome analysis. Outcome-specific denominators, censoring rules, and handling of missing observations are not reported in the registry record. As a result, the completeness and precision of the listed outcomes cannot be assessed from the posted information.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastroesophageal reflux disease (16.7%), ileus (16.7%), aspiration (16.7%), pneumonitis (16.7%), renal and urinary disorders - other (16.7%).

The registry reports participants with serious adverse events by study group: 0 of 6 for Part A Schedule 1, 2 of 6 for Part A Schedule 2, 1 of 6 for Part A Schedule 3, and 5 of 25 for Part B. These are participant counts, not counts of all individual serious events. A participant may experience more than one event, and the registry record does not provide event-level totals in the information available.

Other adverse events are reported for 6 of 6 participants in each Part A group and 24 of 25 in Part B. These figures describe the registry’s separate other-event category; they should not be conflated with serious adverse events. The record lists gastroesophageal reflux disease, ileus, aspiration, pneumonitis, renal and urinary disorders - Other, and gastric ulcer at 16.7% each among the top serious terms. The denominator and group attribution for these term frequencies are not reported in the registry record.

Deaths are recorded as 4, 3, 4, and 5 across the four groups in the same order. These are safety-group figures, not evidence by themselves about cause or treatment attribution. The registry record does not report whether the deaths were considered related to study treatment. Because the groups were not randomized and Part B followed schedule selection, these safety counts are descriptive rather than causal comparisons.

12. What the Result Does, and Does Not, Mean

The registry record documents a phase Ib investigation of three treatment schedules and identifies Schedule 1 as the recommended Phase 2 dosing schedule used in Part B. This provides a record of the schedule-development decision. The numerical dose-limiting toxicity results that would show the primary endpoint by Part A schedule are not reported, so the size and precision of any difference in that endpoint cannot be evaluated.

The posted safety figures describe serious adverse events, other adverse events, and deaths in each group. They establish that these events were recorded, but do not establish that one schedule caused more or fewer events than another. Participants were not randomized, the study was sequential, and Part B used the selected schedule. The groups therefore do not form a like-for-like control comparison.

The record does not provide numerical estimates for the listed response, progression-free survival, or overall survival outcomes. It consequently does not show the magnitude or precision of any observed response or time-to-event result. It also does not provide confidence intervals or inferential tests for those outcomes.

In general, a study’s schedule-selection result, safety counts, and efficacy estimates answer different questions. Schedule selection records which regimen advanced; adverse-event counts describe observed safety events; efficacy estimates would quantify outcomes such as response or time to progression. The registry information supports the first two only at a limited descriptive level, and does not include numerical efficacy estimates.

The findings should therefore be understood as a record of early-phase schedule evaluation, not as a randomized comparison of treatments or as definitive evidence of comparative efficacy. The registry record’s missing endpoint counts, analysis details, and outcome estimates leave substantial uncertainty about the underlying results.

13. Why This Trial Matters Statistically

Early-phase combination studies must make practical decisions about how treatments are sequenced and administered before larger evaluations can proceed. This study addressed that development question by examining three schedules of lutetium Lu 177-PSMA-617 with pembrolizumab, then selecting Schedule 1 for Part B. The registry’s description makes the sequencing explicit: the selected approach gave the radioligand therapy before pembrolizumab.

Statistically, the study illustrates the distinction between a decision endpoint and a comparative treatment effect. Dose-limiting toxicities were intended to inform schedule selection, together with aggregate safety and feasibility. A selected schedule is a useful development outcome, but without the numerical endpoint results it is not possible to assess the underlying differences, uncertainty, or trade-offs among schedules.

The non-randomized sequential design is also important. It makes the record informative about the study’s progression from schedule evaluation to a recommended schedule, but it does not support a clean causal comparison among groups. The descriptive safety counts should be read in that context rather than as evidence that one schedule produced better outcomes.

The registry also lists clinically relevant response and time-to-event outcomes, while not reporting their numerical estimates in the record. This contrast highlights why outcome names alone are not results: estimates, denominators, follow-up rules, and measures of precision are needed for statistical interpretation. The study is therefore most informative as a record of early-phase regimen development, with important limits on what can be learned about comparative effectiveness from the posted results.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations constrain interpretation. The design was non-randomized and sequential, with no randomized control group. Part A schedule groups and the later Part B group are not a like-for-like comparison, so their observed safety counts cannot establish causal differences among schedules. The registry explicitly notes that the arms are not a like-for-like control comparison.

The primary endpoint is the number of reported dose-limiting toxicities in Part A, but numerical counts by schedule are not reported in the registry record. The record identifies Schedule 1 as the recommended Phase 2 dosing schedule without reporting the detailed results or decision criteria underlying that selection. This prevents assessment of the size and precision of the primary endpoint findings.

Although the registry lists secondary outcomes, numerical estimates for response, progression-free survival, overall survival, and other listed outcomes are not reported in the registry record. Confidence intervals, p-values, analysis populations, outcome-specific denominators, and missing-data methods are also not reported. These omissions prevent assessment of precision, completeness, and the statistical methods used for those outcomes.

The safety information is descriptive. The serious adverse event term frequencies are listed as 16.7% each, but the denominator and group attribution are not reported in the registry record. Death counts are listed by group without cause or treatment-related attribution. These details cannot be inferred from the counts alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: 177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer — NCT03805594.
• Registry record last updated 2025-02-25; status last verified 2025-02.
• Results first posted 2025-02-25.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

This completed, non-randomized phase Ib study enrolled 43 participants with metastatic castration-resistant prostate cancer and evaluated lutetium Lu 177-PSMA-617 with pembrolizumab. Part A studied three schedules; Schedule 1, giving the radioligand therapy 28 days before pembrolizumab, was selected as the recommended Phase 2 dosing schedule for Part B.

The primary outcome was the number of reported dose-limiting toxicities in Part A over up to 1 year. Numerical results for that endpoint are not reported in the registry record. Safety counts are reported by group, but the sequential design does not support randomized comparisons. Numerical estimates for the listed response and time-to-event outcomes, along with key analysis details, are also not reported in the registry record.