Combining Immune Checkpoint and Androgen Receptor Inhibitors Yields Positive Responses for mCRPC

Targeted Therapies in OncologyApril 1 2020
Volume 9
Issue 5

Pembrolizumab plus enzalutamide in castration- resistant prostate cancer that exhibited enzalutamide resistance led to positive antitumor signals and a favorable safety profile, according to results of the phase II KEYNOTE-199  trial presented  at the 2020  Genitourinary Cancers Symposium.

Julie N. Graff, MD

Pembrolizumab (Keytruda) plus enzalutamide (Xtandi) in castration- resistant prostate cancer (mCRPC) that exhibited enzalutamide resistance led to positive antitumor signals and a favorable safety profile, according to results of the phase II KEYNOTE-199 trial presented  at the 2020  Genitourinary Cancers Symposium.1

“The addition of pembrolizumab to enzalutamide after enzalutamide resistance showed modest antitumor activity and durable response in patients with RECIST-measurable and bone-predominant mCRPC,” Julie N. Graff, MD, associate professor of medicine at Oregon  Health & Science University  in Portland, said during a presentation of the data.

Cohorts 4 (n = 81) and 5 (n = 45), consisting of patients with RECIST-measurable disease and bone metastases—only/bone-predominant disease, respectively, were included in the current analysis. The primary end point was objective response rate (ORR) by RECIST 1.1 per blinded-independent central review in cohort 4. Secondary end points included disease control rate (DCR), radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) response rate, overall survival (OS), and safety. Median  time from  enrollment to  data cutoff was  15.3 months (range, 6.7-20.7) in cohort 4 and 19.1 months (range, 6.520.9) in cohort 5.

Among patients in cohort 4, 53% had a reduced target lesion, with 24% of patients having ≥30% reduction from baseline. The ORR for this cohort was 12%, composed of 2 complete responses (CRs; 2%) and 8 partial responses (PRs; 10%). Stable disease of any duration occurred  in  38%,  and  the  DCR  for this group was 51%.

The duration of response in cohort 4 was 6.3 months (95% CI, 2.5+ to 13.4), with 60% of responses lasting longer than 6 months.

Patients in cohort 5 had a DCR of 51%, comprised exclusively  of  non-CR  and  non-PR  changes to the target lesion from baseline. In both cohorts, the PSA response rate was 14%, with individual rates of 16% and 9% in cohorts 4 and 5, respectively. Forty percent of patients  had any  PSA decrease from  baseline, with 14% having ≥50% decrease (TABLE).

“For some of the responders, the PSA was nearly a 100% response,” Graff noted, looking at a waterfall plot of PSA response.

Median rPFS in cohort 4 was 4.2 months (95% CI, 2.5-6.0) and 4.4 months (95% CI, 3.4-6.2) in cohort 5. Corresponding rates at  12 months were 17% and 23%.

Median OS was not reached (NR; 95% CI, 15.9NR) in cohort 4 and 18.8 months (95% CI, 14.0NR) in cohort 5. Rates of 12-month OS were 70% and 75%, respectively.

“Of 81 patients enrolled in cohort 4… 13 patients are still on treatment,” Graff said. In cohort  5,  she  said,  “there  are  still  6  patien ts  of  those  45  patients  [who are undergoing] treatment.”

Of treatment-related adverse events, fatigue occurred most often (24% of patients), followed by hyperthyroidism (16%); rash (15%); pruritis, decreased appetite, and maculopapular rash (10% each); diarrhea (9%); and nausea (7%). Another notable but unexpected event was rash, with any-grade events occurring at a rate of 15%, of which 2% were grade ≥3.

“We didn’t think about rash when we used these agents together. The great majority of the time, it  was  controlled  with  oral  or  topical steroids. However, 1 patient did have to receive intravenous steroids,” Graff said.

Immune-mediated events were observed  in 29% of patients, including hypothyroidism in 16%, severe skin reaction in 6%, hyperthyroidism in 3%, and 2% each of adrenal insufficiency, myocarditis, pneumonitis, type 1 diabetes  mellitus, colitis, and hypophysitis.

Patients in cohorts 4 and 5 had median ages of 74 years and 69 years, respectively. Corresponding PSA values at baseline were 31 ng/mL (range, 0.4-1667) and 19 ng/mL (range, 1.4-1750), and two-thirds of patients in both cohorts had a Gleason score ≥8. Most patients had prior  enzalutamide exposure lasting  ≥6 months. The most frequently reported ECOG performance status was 0 in cohort 4 at 53%, followed by 1 in 43% and 2 in 4%. In cohort 5, 58% of patients had an ECOG performance status of 1, followed by 38% at 0 and 4% at 2. More patients in cohort 4 had PD-L1—positive disease at 40% versus 20% in cohort 5.

“I’d like to point out that patients in cohort 4 had a better performance status. They also were more likely to have PD-L1 positivity,” Graff said. “Interestingly, out of 81 patients, 19 had liver metastases, which is a poor prognostic indicator.”

Prior to this analysis, single-agent pembrolizumab demonstrated durable activity in patients with prostate cancer whose tumors were PD-L1 positive in cohorts 1 and 2 of KEYNOTE-199 and in the phase Ib KEYNOTE-028 trial.2,3

Results of a phase II trial of 28 patients that Graff presented at the 2018 American Society of Clinical  Oncology  Annual  Meeting  showed that pembrolizumab  added  to  enzalutamide demonstrated a  25%  radiographic  response  rate for patients with measurable disease and PSA response reduction ≥50% in 18% of patients.4

“The combination is now being studied in a phase III trial, KEYNOTE-641 [NCT03834493], which is for patients who are enzalutamide naïve,” Graff concluded. This trial will evaluate enzalutamide plus either pembrolizumab or placebo in a randomized fashion to determine OS and rPFS in patients with mCRPC.


  1. Graff JN, Antonarakis ES, Hoimes CJ, et al. Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant  metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4-5.  J Clin Oncol. 2020;38(suppl 6; abstr 15). doi: 10.1200/JCO.2020.38.6_suppl.15.
  2. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38(5):395-405. doi: 10.1200/JCO.19.01638.
  3. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29(8):1807-1813. doi: 10.1093/annonc/mdy232.
  4. 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(suppl  15;  abstr  5047). doi: 10.1200/JCO.2018.36.15_suppl.5047.
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