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The last attempt to make immunotherapy work in prostate cancer, this time as early as possible. It was stopped for futility and made rashes and serious side effects much commoner.
KEYNOTE-991 tested whether checkpoint blockade would work if given early, before castration resistance, when the tumour is less heavily pretreated. It randomised 1,251 men with metastatic hormone-sensitive prostate cancer who had not had a next-generation hormonal agent to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles, with enzalutamide 160 mg daily and continuous androgen deprivation.
At the first interim analysis, median follow-up 21.1 months, radiographic progression-free survival was not superior with pembrolizumab: median not reached in either arm, hazard ratio 1.20 (95 percent confidence interval 0.96 to 1.49, p=0.9467). Median overall survival was not reached in either arm, hazard ratio 1.16 (0.88 to 1.53), not formally tested under the multiplicity strategy. The trial did not meet its primary endpoint and was stopped for futility.
Grade 3 or higher adverse events occurred in 61.9 percent with pembrolizumab against 38.1 percent with placebo, and serious adverse events in 40.3 against 23.2 percent. Rash of any grade occurred in 25.1 against 9.3 percent, identified as an additional safety signal for the combination.
With IMbassador250, KEYNOTE-641 and KEYNOTE-921, this closes the unselected checkpoint inhibitor question in prostate cancer. The remaining immunotherapy indication is pembrolizumab for the roughly 3 percent of men with mismatch repair deficient or microsatellite instability high tumours, where selection does the work.
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
1,251 randomised.
median not reached · median not reached
Source| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Radiographic progression-free survivalprimary | Pembrolizumab with enzalutamide and androgen deprivation | 626 | median not reached | 1.2 (0.96 to 1.49) | 0.9467 | link |
| Placebo with enzalutamide and androgen deprivation | 625 | median not reached | ||||
| Grade 3 or higher adverse events | Pembrolizumab with enzalutamide and androgen deprivation | 626 | 61.9% | - | - | link |
| Placebo with enzalutamide and androgen deprivation | 625 | 38.1% |
Shares Androgen receptor pathway inhibitor (ARPI), mCRPC and mHSPC (castration-resistant vs hormone-sensitive prostate cancer), Androgen deprivation therapy (ADT), Metastatic hormone-sensitive prostate cancer.
Shares ARCHES, ENZAMET, Metastatic hormone-sensitive prostate cancer, Androgen deprivation & AR pathway inhibitors.
Shares IMbassador250, KEYNOTE-921, Prostate cancer programmes that failed, and what each failure taught, Prostate cancer.
Shares mCRPC and mHSPC (castration-resistant vs hormone-sensitive prostate cancer), Androgen deprivation therapy (ADT), Metastatic hormone-sensitive prostate cancer, Androgen deprivation & AR pathway inhibitors.
Shares ARCHES, Androgen deprivation & AR pathway inhibitors, Androgen receptor, Prostate cancer.
Shares Androgen receptor pathway inhibitor (ARPI), Prostate cancer programmes that failed, and what each failure taught, Enzalutamide, Androgen receptor.
Shares Metastatic hormone-sensitive prostate cancer, Enzalutamide, Androgen deprivation & AR pathway inhibitors, Prostate cancer.
Shares mCRPC and mHSPC (castration-resistant vs hormone-sensitive prostate cancer), Androgen deprivation therapy (ADT), Metastatic hormone-sensitive prostate cancer, Enzalutamide.