ASCO 2019: Pembrolizumab Plus Olaparib in Docetaxel-Pretreated Patients with mCRPC: Cohort A of KEYNOTE-365 Study

Chicago, IL ( There is currently not enough treatment options in metastatic castrate-resistant prostate cancer (mCRPC) docetaxel-pretreated patients.1 Pembrolizumab is a highly selective humanized monoclonal antibody that blocks the interaction between PD-1 and its ligand, PD-L1, and PD-L2. It has shown activity in patients with heavily pretreated, PD-L1 positive advanced prostate cancer and patients with docetaxel-resistant mCRPC.2,3,4

The KEYNOTE-028 study was conducted to evaluate the safety and efficacy of pembrolizumab in advanced solid tumors. The objective response rate (ORR) was 17.4% among heavily pretreated patients with advanced PD-L1-positive prostate cancer.3 KEYNOTE-199 study aims to evaluate the safety and efficacy of pembrolizumab monotherapy in mCRPC previously docetaxel-treated patients.4

Olaparib is a polyadenosine diphosphate ribose polymerase inhibitor that has shown antitumor activity in patients with previously treated mCRPC.5

In this presentation, data from cohort A (pembrolizumab+olaparib) of the KEYNOTE-365 (NCT02861573) is presented. KEYNOTE-365 is a phase 1b/2 non-randomized, multicenter, multicohort, open-label umbrella study to test various pembrolizumab combinations in mCRPC patients (Figure 1).

The Primary endpoints included: 
  • Safety 
  • Prostate-specific antigen (PSA) response rate (confirmed PSA decrease ≥50%). 
The key secondary endpoints included:
  • Objective response rate (ORR) per RECIST v1.1 criteria (investigator review)
  • Disease control rate: Complete response + partial response + stable disease for more than six months) 
  • Time to PSA progression
  • Composite response rate 
  • Radiographic progression-free survival (rPFS) 
  • Overall survival (OS)
Figure 1 – Study design:

Patient disposition and baseline characteristics are shown in Figure 2 and Table 1, respectively. According to the presented results, the median (95% CI) follow-up was 11 (6-15) mo. Overall, 41 patients had initiated treatment (median age, 69 years; with 41% harboring visceral disease, and 68% having RECIST-measurable disease). The treatment-related adverse events occurred in 39 (95%) patients; most frequent (≥30%) were anemia (37%), fatigue (34%), and nausea (34%) (Table 2). Grade 3-5 treatment-related adverse events occurred in 2 (49%) patients. There was one death caused by a treatment-related adverse event. The immune-mediated adverse events are demonstrated in Table 3.

Figure 2 – Patient disposition:

Table 1 – Patient baseline characteristics:

Table 2 – Treatment-related adverse events of all grades and corresponding grade 3-5 adverse events:

Table 3 – Immune-mediated adverse events:

The confirmed PSA response rate stratified by RECIST is shown in figure 3, demonstrating a 12% response rate in the total population. Time to PSA progression is shown in Figure 4, and the best objective response rate by investigator assessment per RECIST v1.1 is shown in table 4. Lastly, Figure 5 shows the Kaplan-Meier estimates of radiographic progression-free survival based on investigator assessment per PCWG3-Modified RECIST v1.1 and overall survival.

Figure 3 – Confirmed PSA response rates:

Figure 4 – Kaplan Meier estimates of confirmed time to PSA progression:

Table 4 – Confirmed the best objective response rate by investigator assessment per RECIST v1.1:

Figure 5 – Kaplan Meier estimates of a) radiographic progression-free survival based on investigator assessment per RECIST v1.1 and b) Overall survival:

The authors concluded that pembrolizumab + olaparib had shown promising activity in unselected patients with mCRPC who were previously treated with docetaxel, and second-generation hormonal therapy. The observed safety profile for this treatment combination is consistent with the individual profiles of pembrolizumab and olaparib. The results of this study support further evaluation of this treatment combination in mCRPC patients who were previously treated with docetaxel, or with less than one other chemotherapy, or with one or two-second generation hormonal therapies, and whose mCRPC disease is molecularly unselect

The authors pointed out that a randomized phase III study of olaparib with pembrolizumab in unselected mCRPC patients, who were pretreated with enzalutamide or abiraterone and experienced progression on chemotherapy is currently open to enrollment (KEYLYNK-010, NCT03834519). 

Presented by: Evan Y. Yu, MD, Professor, Department of Medicine, Division of Oncology, Seattle Cancer Care Alliance, University of Washington School of Medicine, Seattle, WA

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2019 ASCO Annual Meeting #ASCO19, May 31-June 4, 2019, Chicago, IL USA

  1. NCCN guidelines in Oncology (prostate cancer version 2.2019).
  2. Keytruda (pembrolizumab) injection. Merck Sharp & Dohme corp.
  3. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018 Aug 1;29(8):1807-1813. doi: 10.1093/annonc/mdy232
  4. De Bono J, Goh J, Ojamaa K, et al. KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). DOI: 10.1200/JCO.2018.36.15_suppl.5007 Journal of Clinical Oncology 36, no. 15_suppl (May 20 2018) 5007-5007.
  5. Mateo J, Carreira S, Sandhu S, et al. DNA Repair Defects and Olaparib in Metastatic Prostate Cancer. October 29, 2015 N Engl J Med 2015; 373:1697-1708
    DOI: 10.1056/NEJMoa1506859