Pembrolizumab Plus Enzalutamide Continues to Produce Antitumor Activity in Abiraterone Acetate-Pretreated mCRPC

Leonard J. Appleman, MD, PhD

The combination of pembrolizumab (Keytruda) and enzalutamide (Xtandi) continued to demonstrate antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with abiraterone acetate (Zytiga), according to data from cohort C of the phase 1b/2 KEYNOTE-365 trial (NCT02861573).¹

At a minimum follow-up of 22 months, the confirmed prostate-specific antigen (PSA) response was 26.3% (n = 10/38) in patients with measurable disease per RECIST criteria, 22.2% (n = 14/63) in those with nonmeasurable disease, and 23.8% (n = 24/101) in the total population.

Moreover, the combination induced an objective response rate (ORR) of 10.5% (95% CI, 2.9%-24.8%) in patients with measurable disease (n = 38); this was comprised of 2 complete responses and 2 partial responses. The median duration of response (DOR) with the combination was 11.8 months (range, 4.3-38.3), with 1 patient achieving a response that lasted for longer than 12 months.

“Data from this study continue to support the need for further evaluation of pembrolizumab plus enzalutamide combination therapy in patients with abiraterone acetate–pretreated mCRPC in the prechemotherapy state,” Leonard J. Appleman, MD, PhD, director of the Genitourinary Cancer Disease Center, and associate professor of medicine at the University of Pittsburgh Medical Center, said in a presentation on the data at the 2021 SITC Annual Meeting.

To be eligible for enrollment nonrandomized, multicenter, multicohort, open-label KEYNOTE-365 trial, patients needed to have experienced disease progression within 6 months prior to screening and they needed to have received 4 or more weeks of treatment with abiraterone acetate for metastatic disease. Patients could not have previously received chemotherapy for their disease. Those specifically enrolled to cohort C of the trial must have received 4 or more weeks of abiraterone acetate therapy in the prechemotherapy state.

Study participants were treated with 200 mg of intravenous pembrolizumab every 3 weeks for up to 35 cycles, as well as 160 mg of oral enzalutamide given daily. Treatment continued until confirmed disease progression, intolerable toxicity, or withdrawn consent. Notably, those who discontinued 1 of the study treatments due to treatment-related adverse effects (TRAEs) were permitted to receive the other agent until discontinuation criteria were met.

The primary end points of the study included safety, PSA response rate, and ORR per RECIST v1.1 criteria and blinded independent central review (BICR). Secondary end points included time to PSA progression and overall survival, as well as BICR0- assessed DOR, disease control rate (DCR), and radiographic progression-free survival (rPFS) per PCWG3-modified RECIST v1.1 criteria.

Previous results from cohort C of the study showed that the combination of pembrolizumab and enzalutamide was well tolerated and produced encouraging antitumor activity in those who were chemotherapy naïve and who had previously received abiraterone acetate.^2,3 At the 2021 SITC Annual Meeting, investigators presented updated data from cohort C.

Among the 102 patients enrolled and received the doublet, the median age was 70 years (range, 43-87), with 76.5% of patients aged 65 years or older. The majority of patients had an ECOG performance status of 0 (64.7%) and a negative PD-L1 status (65.7%). The median PSA value among patients was 24.5 ng/mL (range, 0.1-1106.0), and 37.3% had measurable disease per RECISTv1.1 criteria and BICR. Moreover, 99.0% of patients had received prior treatment with abiraterone acetate only and 1.0% previously received enzalutamide only.

Additional data showed that percent change in PSA from baseline in the total population was 72.3% (n = 73/101), and 29.7% of patients (n = 30/101) achieved a PSA reduction of 50% or higher. Moreover, the median time to PSA progression was estimated to be 4.0 months (95% CI, 3.5-4.4).

Among those with measurable disease, the DCR with the combination was 23.7% (95% CI, 11.4%-40.2%). In those with nonmeasurable disease, this rate was 39.1% (95% CI, 27.1%-52.1%); in the total population, the DCR was 33.3% (95% CI, 24.3%-43.4%). The median time to response was 2.0 months (95% CI, 1.9-2.1) among those with measurable disease.

Moreover, 50% of patients with measurable disease (n = 19/38) achieved any reduction in target lesions from baseline, and 23.7% (n = 9/38) achieved a reduction of 30% or higher.

The median rPFS per PCWG3-modified RECIST v1.1 criteria was 6.0 months (95% CI, 4.1-6.3), and median OS was 20.1 months (95% CI, 16.9-25.2).

In terms of safety, 94 patients (92.2%) experienced an any-grade TRAE, and 43 patients (42.2%) reported a grade 3 or higher TRAE. The most common TRAEs of any grade were fatigue (39.2%), nausea (21.6 %), rash (21.6%), decreased appetite (19.6%), diarrhea (19.6%), pruritis (17.6%), asthenia (14.7%), hypothyroidism (13.7%), maculopapular rash (12.7%), and arthralgia (10.8%). The grade 3 to 5 TRAEs that were must frequently reported included rash (7.8%), fatigue (5.9%), maculopapular rash (4.9%), and asthenia (3.9%).

Immune-mediated AEs (IMAEs) of any grade occurred in 37 patients (36.3%) and, grade 3 IMAEs were reported in 22 patients (21.6%). The most common IMAEs of any grade included severe skin reactions (16.7 %), hypothyroidism (13.7%), colitis (3.9%), hyperthyroidism (3.9%), hepatitis (2.0%), infusion reactions (1.0%), myositis (1.0%), pneumonitis (1.0%), and thyroiditis (1.0%). The most frequently experienced grade 3 immune-mediated AEs were severe skin reactions (16.7%), colitis (3.9%), hepatitis (1.0%), and myositis (1.0%).

Four patients died from AEs; 1 of these deaths was determined by a trial investigator to be related to treatment although the cause was unknown.

The safety profile reported in cohort C was generally consistent with the individual safety profiles that have been observed with pembrolizumab and enzalutamide. Incidence of all-grade rash (21.6%) and grade 3 rash (7.8%) was higher than typically reported for the individual agents, but standard-of-care treatment resolved this toxicity.

The doublet will continue to be assessed further as part of the phase 3 KEYNOTE-641 trial (NCT0384493).

References

1. Appleman LJ, Todenhöfer T, Berry W, et al. KEYNOTE-365 cohort C: Pembrolizumab + enzalutamide in patients with abiraterone acetate–pretreated metastatic castration-resistant prostate cancer (mCRPC)—Data after minimum of 22 months of follow-up. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 347.
2. Fong PCC, Retz M, Drakaki A, et al. Keynote-365 cohort C: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(7):171-171. doi:10.1200/JCO.2019.37.7_suppl.171
3. Berry WR, Fong PCC, Piulats JM, et al. KEYNOTE-365 cohort C updated results: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(6):102-102. doi:10.1200/JCO.2020.38.6_suppl.102