The addition of pembrolizumab to enzalutamide did not improve survival compared with enzalutamide alone in patients with metastatic castration-resistant prostate cancer.
Radiographic progression-free survival (rPFS) or overall survival (OS) was not improved by the combination of pembrolizumab (Keytruda) plus enzalutamide (Xtandi) vs enzalutamide monotherapy in patients with metastatic castration-resistant prostate cancer (mCRPC), according to a presentation of the KEYNOTE-641 study (NCT03834493) results at ESMO Congress 2023.1
As a result, the primary end points–OS and rPFS per PCWG-modified RECIST 1.1 by blind independent central review–were not met and the study was stopped for OS futility at the first interim analysis.
“Future studies should focus on patient selection and the identification of positive predictive markers of response, more so than treating all comers, which several studies have shown has not really worked here or they acknowledge it,” Julie N. Graff, MD, Oregon Health & Science University Knight Cancer Institute, said during a presentation of the data.
The median follow-up time at first prespecified interim analysis was 27.6 months (range, 6.1–39.8). At that time, median OS was 24.7 months (95% CI, 22.0-26.8) with placebo plus enzalutamide, compared with 27.3 months (95% CI, 24.5-30.1) with placebo plus enzalutamide (HR, 1.04; 95% CI, 0.88-1.22; P = .66)
Further the 12-month OS rates in the pembrolizumab and placebo arms were 77.9% vs 77.6%, respectively, whereas 18-month rates were 63.6% vs 63.0%.
Subgroup analyses—stratified by age, race, region, ECOG performance status, prior docetaxel for metastatic hormone-sensitive prostate cancer, prior abiraterone therapy, metastases at baseline, and PD-L1 status—also did not demonstrate an OS benefit with pembrolizumab and enzalutamide over placebo and enzalutamide.
Median rPFS with pembrolizumab plus enzalutamide was 10.4 months (95% CI, 8.4-12.5), vs 9.0 months (95% CI, 8.3-11.5) with placebo (HR, 0.98; 95% CI, 0.84-1.14; P = .41).
Similar to OS, there was no rPFS benefit seen across the prespecified subgroup analysis.
The investigators evaluated time to initiation of first subsequent anticancer therapy (TFST) as a secondary end point of the study. Median TFST with pembrolizumab vs placebo was 13.2 months (95% CI, 11.7-15.7) and 12.6 months (95% CI, 11.3-14.2), respectively (HR, 0.95; 95% CI, 0.83-1.09).
Additionally, objective response rate (ORR) served as a secondary end point. The ORR with pembrolizumab plus enzalutamide was 32.3% (95% CI, 26.2%-38.6%), including 17 complete responses (CRs; 7.4%), of which 5 of those patients received prior abiraterone (2.2%); compared with an ORR of 23.9% (95% CI, 18.5%-30.0%) with placebo plus enzalutamide, including 6 CRs (2.7%), of which 2 of those patients received prior abiraterone (0.9%). The disease control rate in each respective arm was 50.0% (95% CI, 43.4%-56.6%) and 46.0% (95% CI, 39.4%-52.8%).
“Interestingly, complete response was higher with pembrolizumab plus enzalutamide. However, it's not clear what the molecular changes were to the tumor that might have allowed this,” Graff said.
Across the pembrolizumab and placebo arms, grade 3 or higher adverse events (AEs) occurred in 55.8% and 41.0% of patients, respectively, whereas grade 3 or higher treatment-related AEs were seen in 31.2% and 10.8% of patients, and 30.9% and 7.4% of patients had immune-mediated AEs and infusion reactions.
The most common AEs occurring in at least 5% of patients in the pembrolizumab and placebo arms included fatigue (22.9% vs 19.8%, respectively), rash (18.7% vs 4.0%), pruritus (11.9% vs 4.5%), nausea (11.1% vs 8.5%), decreased appetite (10.9% vs 9.0%), diarrhea (10.7% vs 7.1%), asthenia (9.9% vs 2.9%), hypothyroidism (9.9% vs 2.9%), maculopapular rash (6.8% vs 0.6%), arthralgia (6.5% vs 4.2%), anemia (5.4% vs 3.7%), and hypertension (4.4% vs 5.2%).
In the randomized, double-blind phase 3 KEYNOTE-641 study, investigators randomized patients 1:1 to receive either 200 mg pembrolizumab IV every 3 weeks (n = 621) or placebo every 3 weeks (n = 623) plus 160 mg oral enzalutamide every day.
To be eligible for the trial, patients had to have confirmed m CRPC; no prior docetaxel for the disease; had no previously received prior enzalutamide, apalutamide (Erleada), or darolutamide (Nubeqa); had an ECOG performance status of 0 or 1; and had a tissue sample available for biomarker assessment. Prior treatment with abiraterone (Zytiga) was permitted.
At baseline, patients in the pembrolizumab arm were a median age of 71 years (median, 45-91). The majority had an ECOG performance status of 0 (58.3%). In total, 85.7% of patients had bone metastases, 12.2% has visceral metastases, and 3.5% had liver metastases. Regarding prior treatment received, 60.5% were given abiraterone and 29.0% were administered docetaxel. Lastly, most patients were PD-L1 negative (70.4%).
Data cutoff was December 12, 2022.
Reference:
1. Graff JN, Burotto M, Fong PC, et al. Pembrolizumab (pembro) plus enzalutamide (enza) for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Randomized double-blind phase III KEYNOTE-641 study. Ann Oncol. 2023;34(S2):S957. doi:10.1016/j.a
Conservative Management Is on the Rise in Intermediate-Risk Prostate Cancer
January 17th 2025In an interview with Peers & Perspectives in Oncology, Michael S. Leapman, MD, MHS, discusses the significance of a 10-year rise in active surveillance and watchful waiting in patients with intermediate-risk prostate cancer.
Read More
Cusnir Explores Impact of ARANOTE Data on ARPI Plus ADT Use in mHSPC
December 31st 2024During an in-person Community Case Forum event in Miami, Florida, Mike Cusnir, MD, discussed the ARANOTE study outcomes presented at ESMO 2024 and how they fit into the treatment paradigm for patients with metastatic hormone-sensitive prostate cancer.
Read More
Imlunestrant Improves PFS in ESR1-Mutant Advanced Breast Cancer
December 13th 2024The phase 3 EMBER-3 trial showed imlunestrant improved PFS over SOC endocrine therapy in ER-positive, HER2-negative advanced breast cancer with ESR1 mutations, though not significantly in the overall population.
Read More
ctDNA Detection Tied to Tumor Burden, Recurrence in HR+ Early Breast Cancer
December 13th 2024A phase 2 trial showed ctDNA detection in HR-positive early breast cancer was linked to larger tumors, higher residual cancer burden, and increased recurrence after neoadjuvant endocrine therapy.
Read More