Clinical Activity With Pembrolizumab/Enzalutamide Emboldens Further Study in mCRPC

The addition of pembrolizumab (Keytruda) to enzalutamide (Xtandi) continues to show encouraging activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who were previously treated with abiraterone acetate (Zytiga), which was revealed in findings from cohort C of the phase Ib/II KEYNOTE-365 trial (NCT02861573) presented by Evan Y. Yu, MD, on the American Urological Association (AUA) Virtual Experience platform for the 2020 AUA Annual Meeting.¹

The rationale for combining pembrolizumab with enzalutamide was born from an observation that patients with mCRPC who were treated with enzalutamide monotherapy displayed increased PD-L1 expression in circulating dendritic cells. This overexpression correlated with worse response rates in patients who had extensive exposure to enzalutamide.²

A phase II single-institution study (NCT02312557) in 2018 reported on the addition of pembrolizumab to enzalutamide for the treatment of patients who progressed on single-agent enzalutamide (n = 28). Of the 12 patients in the study who had measurable disease, 25% achieved a radiographic response rate. Eighteen percent of patients overall exhibited a decrease in prostate-specific antigen (PSA) from baseline of at least 50%. In addition, the overall survival (OS) observed with pembrolizumab plus enzalutamide was 22.2 months. These positive results served as the basis for accruing patients to cohort C of KEYNOTE-365.³

Results from KEYNOTE-365 were initially disclosed in 2019, showing promising clinical activity in cohort C and the combination was well-tolerated in patients.¹

The extended follow-up of cohort C lasted at least 27 weeks. The cohort included 103 patients who had progressive disease (PD) for 8 months or more before screening, and 4 weeks or more treatment with abiraterone before receiving chemotherapy. Pembrolizumab was administered at a dose of 200 mg, 3 times per week, and enzalutamide was administered at 160 mg, once daily. Responses to the combination were assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 based on Prostate Cancer Working Group 3 (PCWG3) guidelines, which state that imaging should occur every 9 weeks through 54 weeks and every 12 weeks thereafter until disease progression. The guidelines also state that PSA must be evaluated every 3 weeks until progression.

The co-primary end points were safety, PSA response rate, and objective response rate (ORR) by RECIST v1.1, The secondary end points were time to PSA progression, disease control rate (DCR), radiographic progression-free survival (rPFS), and OS.

As of the data cutoff date, the confirmed PSA response rate was 21.8% in the overall population. PSA responses were also assessed for patients who had RECIST measurable disease and those who did not. The PSA response rate for patients with measurable disease was 22.5% and 21.3% for those with nonmeasurable disease. Compared with baseline PSA measurements that were both confirmed and unconfirmed, the overall study population demonstrated a 71.3% decrease.

“Notably, a PSA decrease of more than 50% was observed in 29.7% of patients who had a PSA response,” said Yu, clinical research director, Genitourinary Medical Oncology at the Seattle Cancer Care Alliance, and professor, medical oncology, at the University of Washington School of Medicine, in Seattle WA.

Median time to PSA progression among participants who had a PSA response was 3.5 months (95% CI, 2.9-4.0 months) overall. Among patients with measurable disease, the median time to PSA progression was 4.1 months (95% CI, 3.5-5.5 months). Participants with nonmeasurable disease had a median time to PSA progression of 3.0 months (95% CI, 2.8-3.5 months).

In terms of the remaining non-survival secondary outcomes, all data were available for the subgroup of patients with measurable disease. The ORR for this subgroup was 12.0% (95% CI, 2.5%-31.2%) with a DCR of 32,0% (95% CI, 14.9%-53.5%). Two patients with measurable disease had a complete reponse (8.0%), 1 had a partial response (4.0%), and 11 had stable disease (SD; 44.0%). PD was observed in 10 patients (40.0%). Remarkably, 56.0% of patients with measurable disease showed a reduction in target lesion size from baseline and in 24.0% of those patients, the decrease was greater than 30%.

The ORR was not assessed in the overall population by the time of data cutoff, but the DCR was 34.8% (95% CI, 23.7%-47.2%). Eleven patients (15.9%) has SD, whereas 27 patients had PD (39.1%).

Patients with nonmeasurable RECIST also had no ORR assessment. The DCR in this subgroup was 36.4% (95% CI, 22.4%-52.2%). No patients had SD and 17 patients displayed PD (38.6%).

The two survival-related secondary outcomes were also positive in cohort C, showing a median rPFS of 6.1 months (95% CI, 4.4-6.5 months). At 6 months, 55.1% of patients have not yet progressed on treatment with pembrolizumab and enzalutamide. The median OS of 20.4 months (95% CI, 15.5 months to not reached [NR]). After 6 months of pembrolizumab/enzalutamide, 88.2% of patients were still alive.

Treatment-related adverse events (TRAEs) of any grade were observed in 90.2% of patients in the study. TRAEs were grade 3 to 5 in severity in 39.2% of subjects. The most common any-grade TRAEs were fatigue (38.2%) and nausea (21.6%). The most common grade 3 or higher TRAEs were rash (7.8%) and fatigue (5.9%). An increased incidence of rash was observed during the study. Overall, these events occurred in 19.6% of patients and were grade 3 or higher in 7.8% of patients. Standard-of-care treatment for rash was used to resolve these toxicities in most patients, but 9 patients received steroids. One patient experienced treatment-related hemophagocytic lymphohistiocytosis that was resolved with supportive care.

Immune-mediated adverse events (AEs) were reported in 37.3% of patients overall. The most common any-grade immune-mediated AEs included severe skin reaction (17.6%), and hypothyroidism (14.7%). The most common grade 3 to 5 immune-mediated AEs were severe skin reactions (17.6%), and colitis (2.9%).

One patient in the study died as a result of an AE, which was believed to be related to treatment. The cause was unknown.

Pembrolizumab/enzalutamide was overall well-tolerated in patients with mCRPC with a profile consistent with the prior known safety and tolerability of both agents alone.

The positive safety and efficacy outcomes witnessed in the KEYNOTE-365 study support further assessment of the combination of pembrolizumab and enzalutamide in a larger population of patients with mCRPC. Such an evaluation is underway in the phase III randomized, double-blinded KEYNOTE-641 study of enzalutamide with or without pembrolizumab in patients with mCRPC who are intolerant to or progressed on abiraterone acetate without having chemotherapy. The study (NCT03834493) aims to enroll 1200 participants.

_Reference:

_{Yu, EY, Fong P, Piulats JM, et al. Pembrolizumab plus enzalutamide in abiraterone-pretreated patients with metastatic castration-resistant prostate cancer: updated results from keynote-365 cohort c. J Urol. 2020; 203(suppl 4):PD16-12. doi:10.1097/JU.0000000000000859.012}

_{Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in enzalutamide resistant prostate cancer. Oncotarget. 2015; 6:234-242. doi:10.18632/oncotarget.2703}

_{Graff JN, Alumkal JJ, Thompson RF, et al. Pembrolizumab (pembro) plus enzalutamide (enz) in metastatic castration resistant prostate cancer (mCRPC): Extended follow up. J Clin Oncol. 2018; 36(15):5047-5047.}