Home Prostate / Prostate Cancer Combining Immune Checkpoint and Androgen Receptor Inhibitors Yields Positive Responses for mCRPC

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


Julie N. Graff, MD
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.

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

This site uses Akismet to reduce spam. Learn how your comment data is processed.