REACTT: Tadalafil Once Daily or On Demand After Bilateral Nerve-Sparing Radical Prostatectomy
REACTT was a multicenter, double-blind, double-dummy, placebo-controlled randomized trial of tadalafil 5 mg daily or 20 mg on demand versus placebo for 9 months after bilateral nerve-sparing radical prostatectomy in 423 men aged 68 or younger with normal preoperative erectile function. After a 6-week washout, an IIEF-EF score of 22 or higher occurred in 20.9%, 16.9% and 19.1% of the three arms, so neither tadalafil regimen met the primary endpoint of improved unassisted erectile function, although daily tadalafil improved drug-assisted function and reduced penile length loss.[1]
- Design and population
- Multicenter, double-blind, double-dummy, placebo-controlled randomized trial. 423 men aged 68 or younger with localized prostate cancer (Gleason score 7 or lower) and normal preoperative erectile function who underwent bilateral nerve-sparing radical prostatectomy at 50 centers in nine European countries and Canada.
- Arms
- Tadalafil 5 mg once daily versus tadalafil 20 mg on demand versus placebo
- Report and follow-up
- 2013 · 9-month double-blind treatment, 6-week washout, 3-month open-label treatment (13.5 months)
| Endpoint | Results | Effect | Finding |
|---|---|---|---|
| IIEF-EF of 22 or higher after 6-week drug-free washout (month 10.5), tadalafil once daily versus placebo | 20.9% (n=139) vs 19.1% (n=141) | OR 1.1; CI 0.6–2.1; P 0.675 | Not met |
| IIEF-EF of 22 or higher after 6-week drug-free washout (month 10.5), tadalafil on demand versus placebo | 16.9% (n=142) vs 19.1% (n=141) | OR 0.9; CI 0.5–1.7; P 0.704 | Not met |
Harms: Serious adverse events during double-blind treatment and washout: 2/139 vs 3/143 vs 10/141; Discontinued double-blind treatment because of an adverse event: 10/139 vs 6/143 vs 4/141; Any non-serious adverse event during double-blind treatment and washout: 50/139 vs 52/143 vs 40/141
Design
Men were enrolled between November 2009 and August 2011 at 50 centers in nine European countries and Canada. Eligible men had organ-confined, non-metastatic prostate cancer (Gleason score 7 or lower, PSA below 10 ng/mL) and a preoperative IIEF-EF score of at least 22, measured after the cancer diagnosis and within 6 weeks before surgery. After surgery they had to have erectile dysfunction, defined by a patient-reported residual erection function score of 3 or less; at randomization 83.9% had severe dysfunction (IIEF-EF 0–10).[2] The registry record also excluded men with diabetes, previous PDE5 inhibitor use, radiation or hormonal therapy for prostate cancer, or previous prostatic surgery. Of 583 men screened, 423 were randomized.[3]
Treatment began within 6 weeks after surgery with matching tablets: tadalafil 5 mg daily plus placebo on demand, tadalafil 20 mg on demand plus placebo daily, or placebo for both.[1] On-demand dosing allowed up to 3 tablets a week and no more than 1 a day.[4] Nine months of double-blind treatment were followed by a 6-week drug-free washout and then 3 months of open-label tadalafil 5 mg daily in all patients.[1]
The primary endpoint was the proportion of men with an IIEF-EF score of 22 or higher after the washout, a measure of unassisted function. Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3) and penile length.[1] The prespecified comparisons were each tadalafil arm against placebo, the planned sample size was 412, and the analysis population excluded one on-demand patient with no post-baseline data.[2]
Results
After the washout, 20.9% of men previously assigned to daily tadalafil, 16.9% previously assigned to tadalafil on demand and 19.1% previously assigned to placebo had an IIEF-EF score of 22 or higher (odds ratio 1.1, 95% CI 0.6–2.1, P = 0.675 for daily tadalafil; 0.9, 95% CI 0.5–1.7, P = 0.704 for on demand).[1] The analysis populations were 139, 142 and 141 men. The primary endpoint was not met for either regimen.[1][3]
At the end of the 9 months of treatment, while men were still taking the drug, 25.2%, 19.7% and 14.2% had an IIEF-EF score of 22 or higher (odds ratio 2.15, 95% CI 1.16–3.99, P = 0.016 for daily tadalafil versus placebo; on demand versus placebo 1.50, 95% CI 0.79–2.85, P = 0.210).[2][3] The mean IIEF-EF improvement exceeded placebo by 2.80 points with daily tadalafil (95% CI 0.76–4.83; P = 0.007) and by 1.59 points with on-demand tadalafil (95% CI −0.41 to 3.60; P = 0.118).[3] Improvement exceeded the 4-point minimally important difference in both tadalafil arms, and SEP-3 improved significantly over placebo with daily tadalafil only (P = 0.019).[1]
Daily tadalafil reduced the loss of stretched penile length by a least-squares mean of 4.1 mm versus placebo at 9 months (95% CI 0.4–7.8 mm; P = 0.032); on-demand tadalafil had no significant effect. At the end of double-blind treatment, 34.2% of men on daily tadalafil, 50.0% on tadalafil on demand and 56.5% on placebo reported no morning erections; the distribution of Standardized Morning Erection Question responses across arms differed (P = 0.045).[5]
A prespecified secondary analysis measured time to recovery (IIEF-EF of 22 or higher) during double-blind treatment. Recovery occurred at some point in 29.5% of men on daily tadalafil, 23.9% on tadalafil on demand and 18.4% on placebo; fewer than half recovered in any arm, so the median time could not be estimated. A quarter of men reached recovery by 5.8, 9.0 and 9.3 months, respectively. The hazard ratio against placebo was 1.90 for daily tadalafil (95% CI 1.16–3.12; P = 0.011) and 1.47 for tadalafil on demand (95% CI 0.88–2.47; P = 0.140).[2]
After 3 months of open-label daily tadalafil in all arms, 32.4%, 33.1% and 27.0% had an IIEF-EF score of 22 or higher, without a significant difference between arms (odds ratio 1.34, 95% CI 0.79–2.28, for the daily arm versus placebo).[3] In a post hoc analysis using the stricter standard of returning to the preoperative IIEF-EF category, 22.3% of the daily arm, 11.3% of the on-demand arm and 7.8% of the placebo arm had done so at the end of double-blind treatment.[6] The difference did not persist after the washout.[6]
On the patient-rated EPIC-26 sexual domain, daily tadalafil improved scores by 9.6 points more than placebo at the end of double-blind treatment (95% CI 3.1–16.0; P = 0.004); on-demand tadalafil did not differ significantly, and the daily-arm difference was 3.2 points (95% CI −4.3 to 10.7) after open-label treatment. Treatment satisfaction (EDITS total score, 0–4 scale) was higher than with placebo by 0.33 points for daily tadalafil (95% CI 0.10–0.56; P = 0.005) and 0.23 for on demand (95% CI 0.01–0.45; P = 0.041). In an exploratory age-stratified analysis, EPIC-26 urinary incontinence scores improved with daily tadalafil only in men aged 61 to 68, with an overall treatment effect of 8.3 points (95% CI 0.4–16.1; P = 0.040).[4]
Among 332 men with complete data, a post hoc decision-tree analysis found higher presurgery sexual desire associated with higher IIEF-EF at the end of double-blind treatment (mean 14.9 with an IIEF item 12 score of 3.5 or higher versus 11.1 below 3.5). In the 198-man branch with high presurgery desire and confidence, mean IIEF-EF at the end of double-blind treatment was 17.6 with daily tadalafil (n = 67) and 14.3 with on-demand tadalafil or placebo pooled (n = 131). After the washout, postsurgery treatment group had no relevant effect in the model.[7]
Surgery and treatment delivery
Surgery was not randomized. Of 422 treated men, 189 had open surgery, 115 robot-assisted laparoscopy, 88 conventional laparoscopy and 30 another approach. In a model adjusted for treatment, country, age group, nerve-sparing score and approach, the odds of an IIEF-EF score of 22 or higher after the washout were about twice as high after robot-assisted laparoscopy as after open surgery (odds ratio 2.42, 95% CI 1.24–4.72; P = 0.029), and time to recovery during double-blind treatment was shorter (hazard ratio 1.92, 95% CI 1.17–3.15; P = 0.010). Conventional laparoscopy showed no favorable effect compared with open surgery. The authors state that the trial was not designed for these analyses.[8]
Surgeons graded nerve sparing on a 1 to 4 scale for each neurovascular bundle (1 complete preservation, 4 complete resection); a total of 2 was perfect, and men with a total score above 4 were excluded, so most enrolled men had a perfect score.[7]
In the on-demand arm, mean use was 1.5 tablets (SD 0.95) of 20 mg per week.[2] Completion of double-blind treatment was 114 of 139 men in the daily arm, 122 of 143 in the on-demand arm and 115 of 141 in the placebo arm.[3]
Adverse events
The registry record reports serious adverse events during double-blind treatment and washout in 2 of 139 men on daily tadalafil, 3 of 143 on tadalafil on demand and 10 of 141 on placebo. Adverse events led to discontinuation of double-blind treatment in 10, 6 and 4 men, respectively, and 50, 52 and 40 men had at least one non-serious event. The most frequently listed non-serious events were headache (5, 11 and 6 men), nasopharyngitis (5, 5 and 3), back pain (5, 5 and 3), dyspepsia (5, 5 and 1) and myalgia (5, 5 and 1). Penile curvature was listed as a non-serious event in one man in each tadalafil arm and none on placebo.[3]
Limitations
Nine months of treatment was too short to judge recovery: fewer than half the men in any arm reached an IIEF-EF score of 22 or higher during treatment, and the authors could not exclude that spontaneous recovery in the placebo arm would erase the early difference by 2 years.[2] The washout lasted 6 weeks, and open-label daily tadalafil in all patients ended the placebo comparison at month 10.5.[1]
The population was selected: men aged 68 or younger (mean age 57.9 years) with normal preoperative function, organ-confined cancer of Gleason score 7 or lower and no diabetes.[1][3] Baseline IIEF-EF was assessed after the cancer diagnosis, when anxiety may affect the score, and the nerve-sparing score was a surgeon-rated measure.[7] Surgeon volume and learning curve were not accounted for in the surgical-approach analyses.[7]
The quality-of-life analyses applied no multiplicity adjustment.[4] The decision-tree and return-to-baseline analyses were post hoc. Of the men who started double-blind treatment, 25 of 139 (daily), 21 of 143 (on demand) and 26 of 141 (placebo) did not complete it.[3] The trial was funded by Eli Lilly and Company.[2]
In conversation
- Extends Sildenafil Pivotal Trials (1998). Sildenafil trials established on-demand PDE5 inhibitor efficacy in erectile dysfunction; REACTT tested tadalafil started after prostatectomy for unassisted recovery.
REACTT measured recovery of unassisted function after drug withdrawal as its primary endpoint, whereas its reports on penile length, time to recovery, EPIC-26 scores and satisfaction measure effects during treatment. An earlier nine-month randomized trial of vardenafil, started within 2 weeks after surgery, likewise improved drug-assisted function on demand without a significant effect on unassisted function after washout.[4]
Guidelines and approvals
- AUA (Erectile Dysfunction guideline, 2018). Men who desire preservation of erectile function after radical prostatectomy or radiotherapy should be told that early PDE5 inhibitor use may not improve spontaneous, unassisted erectile function . The guideline's rationale cites REACTT among the randomized trials that did not show improved unassisted function with early PDE5 inhibitor use, and reports a pooled relative risk of 1.0 (95% CI 0.66–1.64) in its meta-analysis of three placebo-controlled trials in men after radical prostatectomy.[9]
- EAU Prostate Cancer guideline (limited update, March 2026). The text describes the 423-man trial and a 9.6-point greater EPIC sexual domain improvement with daily tadalafil (95% CI 3.1–16.0) at 9 months that vanished after the end of the study, and concludes that, based on discordant results, no clear recommendation is possible, although a trend exists for early use of PDE5 inhibitors after radical prostatectomy. The passage carries no strength rating.[10]
Report history
| Published | Report | Cutoff | Headline results | Citation |
|---|---|---|---|---|
| 2013-10-13 | Initial report · primary | — | IIEF-EF of 22 or higher after 6-week drug-free washout (month 10.5), tadalafil once daily versus placebo: 20.9% (n=139) vs 19.1% (n=141); OR 1.1; CI 0.6–2.1; P 0.675 Not met IIEF-EF of 22 or higher after 6-week drug-free washout (month 10.5), tadalafil on demand versus placebo: 16.9% (n=142) vs 19.1% (n=141); OR 0.9; CI 0.5–1.7; P 0.704 Not met IIEF-EF of 22 or higher at the end of 9-month double-blind treatment (month 9): 25.2% (n=139) vs 19.7% (n=142) vs 14.2% (n=141); OR 2.15; CI 1.16–3.99; P 0.016 Mean change in IIEF-EF score from baseline to month 9; once daily versus placebo: 7.73 vs 6.53 vs 4.93; difference 2.8; CI 0.76–4.83; P 0.007 Sexual Encounter Profile question 3 (successful intercourse) at month 9, treatment effect versus placebo: Significant for once daily only; the 23% minimally important difference was exceeded in the once-daily arm only.; P 0.019 Reduction in penile length loss at month 9, once daily versus placebo (least-squares mean): Millimeters of length retained. Significant for once daily only.; difference 4.1; CI 0.4–7.8; P 0.032 IIEF-EF of 22 or higher after 3 months of open-label daily tadalafil in all arms (month 13.5): 32.4% (n=139) vs 33.1% (n=142) vs 27.0% (n=141); OR 1.34; CI 0.79–2.28; P 0.273 | Montorsi F, Brock G, Stolzenburg JU, et al. "Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)." *Eur Urol.* 2014;65(3):587-596. doi:10.1016/j.eururo.2013.09.051 DOI |
| 2014-08-26 | Time to recovery · secondary | — | Hazard of reaching IIEF-EF of 22 or higher during double-blind treatment, once daily versus placebo (Cox model): 29.5% vs 23.9% vs 18.4%; HR 1.9; CI 1.16–3.12; P 0.011 Months until 25% of patients reached IIEF-EF of 22 or higher (Kaplan-Meier): 5.8 months vs 9.0 months vs 9.3 months; — Improved by at least one IIEF-EF severity category during double-blind treatment: 41.0% vs 38.7% vs 22.7%; — | Moncada I, de Bethencourt FR, Lledó-García E, et al. "Effects of tadalafil once daily or on demand versus placebo on time to recovery of erectile function in patients after bilateral nerve-sparing radical prostatectomy." *World J Urol.* 2015;33(7):1031-1038. doi:10.1007/s00345-014-1377-3 DOI |
| 2015-03-24 | Penile length and morning erections · secondary | — | Greater retention of stretched penile length at the end of double-blind treatment, once daily versus placebo (least-squares mean): Millimeters. No significant effect for on demand versus placebo.; difference 4.1; CI 0.4–7.8; P 0.032 Patients reporting no morning erections at the end of double-blind treatment: 34.2% vs 50.0% vs 56.5%; P 0.045 | Brock G, Montorsi F, Costa P, et al. "Effect of Tadalafil Once Daily on Penile Length Loss and Morning Erections in Patients After Bilateral Nerve-sparing Radical Prostatectomy: Results From a Randomized Controlled Trial." *Urology.* 2015;85(5):1090-1096. doi:10.1016/j.urology.2014.11.058 DOI |
| 2015-04-12 | Quality of life and satisfaction · pro | — | Least-squares mean change in EPIC-26 sexual domain score (0-100 scale) at the end of double-blind treatment; difference for once daily versus placebo: 27.5 vs 20.7 vs 18.0; difference 9.6; CI 3.1–16; P 0.004 EDITS total score (0-4 scale) at the end of double-blind treatment; difference for once daily versus placebo: On demand versus placebo: 0.23 (95% CI 0.01-0.45; P=0.041). After open-label treatment only once daily remained significant (P=0.035).; difference 0.33; CI 0.1–0.56; P 0.005 Overall treatment effect of once daily versus placebo across all visits in men aged 61 to 68 years: Age-by-treatment interaction P=0.084; not seen in men younger than 61.; difference 8.3; CI 0.4–16.1; P 0.040 | Patel HR, Ilo D, Shah N, et al. "Effects of tadalafil treatment after bilateral nerve-sparing radical prostatectomy: quality of life, psychosocial outcomes, and treatment satisfaction results from a randomized, placebo-controlled phase IV study." *BMC Urol.* 2015;15:31. doi:10.1186/s12894-015-0022-9 DOI |
| 2015-04-20 | Surgical approach · post-hoc | — | IIEF-EF of 22 or higher at the end of washout, robot-assisted laparoscopy versus open surgery: Model adjusted for treatment, country, age group, nerve-sparing score and surgical approach. No favorable effect of conventional laparoscopy versus open surgery.; OR 2.42; CI 1.24–4.72; P 0.029 Hazard of recovery during double-blind treatment, robot-assisted laparoscopy versus open surgery (post hoc Cox model): —; HR 1.92; CI 1.17–3.15; P 0.010 | Stolzenburg JU, Graefen M, Kriegel C, et al. "Effect of surgical approach on erectile function recovery following bilateral nerve-sparing radical prostatectomy: an evaluation utilising data from a randomised, double-blind, double-dummy multicentre trial of tadalafil vs placebo." *BJU Int.* 2015;116(2):241-251. doi:10.1111/bju.13030 DOI |
| 2016-03-03 | Decision-tree predictors · post-hoc | — | Mean IIEF-EF at the end of double-blind treatment among 332 complete cases, by presurgery sexual desire (IIEF item 12 of 3.5 or higher versus below 3.5): 14.9 (n=210) versus 11.1 (n=122). Descriptive decision-tree split, not a confirmed predictor.; — Mean IIEF-EF in the 198-man high-presurgery-desire-and-confidence branch, tadalafil once daily versus on-demand tadalafil and placebo pooled, at the end of double-blind treatment: 17.6 (n=67) versus 14.3. In the washout model, postsurgery treatment group had no relevant impact on IIEF-EF.; — | Montorsi F, Oelke M, Henneges C, et al. "Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy." *Eur Urol.* 2016;70(3):529-537. doi:10.1016/j.eururo.2016.02.036 DOI |
| 2016-03-25 | Return to baseline · post-hoc | — | Returned to preoperative IIEF-EF category at the end of double-blind treatment: 22.3% vs 11.3% vs 7.8%; — Descriptive | Mulhall JP, Brock G, Oelke M, et al. "Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy-Results from a Randomized Controlled Trial (REACTT)." *J Sex Med.* 2016;13(4):679-683. doi:10.1016/j.jsxm.2016.01.022 DOI |
References
1. Montorsi F, Brock G, Stolzenburg JU, et al. "Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)." Eur Urol. 2014;65(3):587-596. doi:10.1016/j.eururo.2013.09.051
2. Moncada I, de Bethencourt FR, Lledó-García E, et al. "Effects of tadalafil once daily or on demand versus placebo on time to recovery of erectile function in patients after bilateral nerve-sparing radical prostatectomy." World J Urol. 2015;33(7):1031-1038. doi:10.1007/s00345-014-1377-3
3. Eli Lilly and Company. "A Study of Tadalafil After Radical Prostatectomy." ClinicalTrials.gov record NCT01026818, results posted November 2013. clinicaltrials.gov/study/NCT01026818
4. Patel HR, Ilo D, Shah N, et al. "Effects of tadalafil treatment after bilateral nerve-sparing radical prostatectomy: quality of life, psychosocial outcomes, and treatment satisfaction results from a randomized, placebo-controlled phase IV study." BMC Urol. 2015;15:31. doi:10.1186/s12894-015-0022-9
5. Brock G, Montorsi F, Costa P, et al. "Effect of Tadalafil Once Daily on Penile Length Loss and Morning Erections in Patients After Bilateral Nerve-sparing Radical Prostatectomy: Results From a Randomized Controlled Trial." Urology. 2015;85(5):1090-1096. doi:10.1016/j.urology.2014.11.058
6. Mulhall JP, Brock G, Oelke M, et al. "Effects of Tadalafil Once-Daily or On-Demand vs Placebo on Return to Baseline Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy-Results from a Randomized Controlled Trial (REACTT)." J Sex Med. 2016;13(4):679-683. doi:10.1016/j.jsxm.2016.01.022
7. Montorsi F, Oelke M, Henneges C, et al. "Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy." Eur Urol. 2016;70(3):529-537. doi:10.1016/j.eururo.2016.02.036
8. Stolzenburg JU, Graefen M, Kriegel C, et al. "Effect of surgical approach on erectile function recovery following bilateral nerve-sparing radical prostatectomy: an evaluation utilising data from a randomised, double-blind, double-dummy multicentre trial of tadalafil vs placebo." BJU Int. 2015;116(2):241-251. doi:10.1111/bju.13030
9. Burnett AL, Nehra A, Breau RH, et al. "Erectile Dysfunction: AUA Guideline." J Urol. 2018;200(3):633-641. doi:10.1016/j.juro.2018.05.004
10. Cornford P, Tilki D, van den Bergh RCN, et al. "EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer." Limited update, March 2026, section 8.3.2.a. EAU Guidelines Office, Arnhem. uroweb.org/guidelines/prostate-cancer