PORTEC-4a
Molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer (PORTEC-4a)
Phase 3N = 569NCT03469674
- Population
- Early-stage high-intermediate-risk endometrial cancer, age 18 or older, WHO performance status 0-2; 564 eligible and evaluable patients analysed
- Design
- Randomised, open-label, phase 3, multicentre, non-inferiority trial across eight European countries. After surgery, women were randomised 2:1 to adjuvant treatment by molecular integrated risk profile or to standard vaginal brachytherapy (biased-coin minimisation; stratified by centre, grade and lymphadenectomy). Molecular profile group: favourable profile (POLE-mutated, or no specific molecular profile with CTNNB1 wild type) observation; intermediate profile (mismatch repair deficient, or NSMP with CTNNB1 mutated) vaginal brachytherapy, 21 Gy in three fractions of 7 Gy; unfavourable profile (p53 abnormal, or substantial lymphovascular space invasion, or L1CAM overexpression) pelvic radiotherapy, 45.0 to 48.6 Gy. Enrolled 1 June 2016 to 24 December 2021: 569 patients enrolled; the final combined cohort of 564 eligible and evaluable patients (367 and 197) includes 23 favourable-profile patients from PORTEC-4. In the molecular profile group 168 (46%) had a favourable, 148 (40%) an intermediate and 51 (14%) an unfavourable profile. ClinicalTrials.gov lists an estimated enrolment of 550.
- Primary endpoint
- Vaginal recurrence
- Arms
- Standard vaginal brachytherapy (control, n = 197): Vaginal brachytherapy (standard treatment)
- Molecular profile-based treatment (experimental, n = 367): Observation (favourable), vaginal brachytherapy 21 Gy in three fractions (intermediate) or pelvic radiotherapy 45.0 to 48.6 Gy (unfavourable) according to molecular integrated risk profile
- People
- van den Heerik ASVM
Vaginal recurrenceHR 2.71 (95% CI 0.79–9.34)Δ 60-month Vaginal recurrence+2.9 pointsVaginal recurrenceHR 3.97 (95% CI 0.48–32.95)Δ 60-month Vaginal recurrence+3.2 pointsΔ Grade 3 or worse genitourinary toxicity−1 points
Show the numbers
| Endpoint | Analysis | Molecular profile-based treatment | Standard vaginal brachytherapy | Effect |
|---|---|---|---|---|
| Vaginal recurrenceOverall 5-year cumulative incidence of vaginal recurrence as first event (primary endpoint); non-inferiority tested against a predefined margin of 7.0% | primarymedian follow-up 58.1 monthsvan 2026 | 4.5% at 5 y (2.23–6.76%) | 1.6% at 5 y (0.00–3.32%) | HR 2.71 (95% CI 0.79–9.34)P=0.005The p-value is the published non-inferiority p (0.005): the upper bound of the one-sided confidence interval of the difference (5.3%) was below the predefined margin of 7.0%. Final cohort of 564 eligible and evaluable patients (367 and 197) after adding 23 favourable-profile patients from PORTEC-4; 569 patients were enrolled in PORTEC-4a. |
| Vaginal recurrenceFavourable molecular profile (POLE-mutated or NSMP with CTNNB1 wild type); observation in the molecular profile group, vaginal brachytherapy in the standard group5-year vaginal recurrence in patients with a favourable molecular profile (second primary analysis) | primarymedian follow-up 58.1 monthsvan 2026 | 4.1% at 5 y (0.81–7.37%) | 0.9% at 5 y (0.00–2.78%) | HR 3.97 (95% CI 0.48–32.95)The abstract describes this as the second primary analysis. The confidence interval of the hazard ratio is wide. |
| Grade 3 or worse genitourinary toxicityFinal cohort of eligible and evaluable patients (367 and 197)Grade 3 or above genitourinary toxicity | primaryvan 2026 | 1% | 2% | Four of 367 patients in the molecular profile group versus four of 197 in the standard group. Five serious adverse events occurred, one possibly treatment-related (vaginal scar dehiscence); no treatment-related deaths. |
| Endpoint | Analysis | Molecular profile-based treatment | Standard vaginal brachytherapy | Effect |
|---|---|---|---|---|
| Vaginal recurrenceOverall 5-year cumulative incidence of vaginal recurrence as first event (primary endpoint); non-inferiority tested against a predefined margin of 7.0% | primarymedian follow-up 58.1 monthsvan 2026 | 4.5% at 5 y (2.23–6.76%) | 1.6% at 5 y (0.00–3.32%) | HR 2.71 (95% CI 0.79–9.34)P=0.005The p-value is the published non-inferiority p (0.005): the upper bound of the one-sided confidence interval of the difference (5.3%) was below the predefined margin of 7.0%. Final cohort of 564 eligible and evaluable patients (367 and 197) after adding 23 favourable-profile patients from PORTEC-4; 569 patients were enrolled in PORTEC-4a. |
| Vaginal recurrenceFavourable molecular profile (POLE-mutated or NSMP with CTNNB1 wild type); observation in the molecular profile group, vaginal brachytherapy in the standard group5-year vaginal recurrence in patients with a favourable molecular profile (second primary analysis) | primarymedian follow-up 58.1 monthsvan 2026 | 4.1% at 5 y (0.81–7.37%) | 0.9% at 5 y (0.00–2.78%) | HR 3.97 (95% CI 0.48–32.95)The abstract describes this as the second primary analysis. The confidence interval of the hazard ratio is wide. |
| Grade 3 or worse genitourinary toxicityFinal cohort of eligible and evaluable patients (367 and 197)Grade 3 or above genitourinary toxicity | primaryvan 2026 | 1% | 2% | Four of 367 patients in the molecular profile group versus four of 197 in the standard group. Five serious adverse events occurred, one possibly treatment-related (vaginal scar dehiscence); no treatment-related deaths. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| Vaginal recurrence | 2.71 | 0.79–9.34 |
| Vaginal recurrence | 3.97 | 0.48–32.95 |
Appears in
Sources
van den Heerik ASVM, Horeweg N, Haverkort MAD, Kuijsters N, Kommoss S, Koppe FLA, et al. Molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer (PORTEC-4a): results of a randomised, open-label, phase 3, multicentre, non-inferiority trial. Lancet Oncol. 2026;27(1):23-35.