ASCO GU 2019: Pembrolizumab Plus Olaparib Treatment for Docetaxel-Pretreated mCRPC Patients - KEYNOTE 365 Cohort A

San Francisco, CA (UroToday.com) KEYNOTE 365 is a phase 1b/2 study composed of three treatment strategies all including pembrolizumab for patients with metastatic castration-resistant prostate cancer.  Cohort A combines pembrolizumab with olaparib, while cohort B combines pembrolizumab with docetaxel, and cohort C combines pembrolizumab with enzalutamide. Single-agent immune checkpoint inhibitors have had limited success in prostate cancer. In select population of patients with unique biomarkers such as MSI-H tumors, PD1/PDL1 agents have seen minimal success – in 10 MSI high patients, 2/10 had a radiographic PR and 3/10 have had PSA decline of more than 60%.1 However, in unselected patients such as KEYNOTE 199, objective response rates were between 3-5% of patients.2 Olaparib has a similar story in unselected patients – however, after careful biomarker selection such as choosing patients with DNA repair defects, up to 88% of patients may have a response (TOPARP).3 However, for those who were biomarker negative, there was only a 6% (2/33) response rate.3 Combining olaparib with a PD1/PDL1 agent may enhance anti-tumor activity – in a phase II study of durvalumab in combination with olaparib, preliminary data showed that 50% of patients (3/6) had a PSA decline of 50% with one patient achieving a partial response.4
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This abstract provides data from cohort A of KEYNOTE-365, a phase 1b/2 umbrella study which treated patients with pembrolizumab 200 mg every three weeks in combination with olaparib 400 mg twice daily. Patients included in this cohort were heavily pretreated with at least 1 prior line of chemotherapy (allowed up to two lines of chemotherapy), and could have had up to two prior 2nd generation androgen antagonists. The primary endpoints were safety and PSA response rate defined as a confirmed PSA50 (confirmed PSA decline ≥50%).  Important secondary endpoints included objective response rates (ORR) by RECIST 1.1, disease control rate (SD, PR, CR ≥6 months), time to PSA progression, OS, rPFS, and decrease in CTC counts from more than 5 cells to less than 5 cells. 
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At the time of this abstract, median follow up time was 11 months for 41 patients who had initiated treatment. In terms of baseline characteristics, the median age was 69 and most patients had an ECOG PS of 0 or 1. 27% of patients were classified as PD-L1 positive based on a combined positive score of ≥1 and notably 0% were defined as having homologous recombination deficiency.
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12% (5/41) patients had a confirmed PSA response and 7% (2/28) patients with measurable disease had a confirmed objective response by RECIST 1.1. The disease control rate was 32% (9/28) in those with measurable disease and 23% (3/13) for those without measurable disease. Median time to radiographic progression-free survival was 5 months and median overall survival was 14 months.
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In this heavily pre-treated population of patients with mCRPC, while not many objective radiographic responses were seen (2/28), combination olaparib/pembrolizumab was able to provide disease control in 29% (12/41) of patients. It is interesting that there were no patients with homologous recombination deficiency – prior studies have described the incidence of HRD to be in the range of 10-25% depending on Gleason grade.5 This study continues to enroll to a goal of 100 patients and a separate study which includes unselected patients after enzalutamide or abiraterone will also be opening for accrual (KEYLYNK-010).


Presented By: Evan Y. Yu, MD, Professor, Department of Medical Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Assistant Fellowship Director, Hematology and Oncology Fellowship Training Program, University of Washington and Fred Hutchinson Cancer Research Center, Clinical Trials Core Director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance
Discussant: Nicholas J. van As, MBBCH, MRCP, FRCR, MD(res)

Written By: Jason Zhu, MD. Fellow, Division of Hematology and Oncology, Duke University, Twitter: @TheRealJasonZhu at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA

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References:
  1. Abida W, Cheng ML, Armenia J, et al. Microsatellite instability in prostate cancer and response to immune checkpoint blockade. American Society of Clinical Oncology; 2018.
  2. De Bono JS, Goh JC, Ojamaa K, et al. KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). American Society of Clinical Oncology; 2018.
  3. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. New England Journal of Medicine 2015;373:1697-708.
  4. Karzai F, Madan RA, Owens H, et al. A phase II study of the anti-programmed death ligand-1 antibody durvalumab (D; MEDI4736) in combination with PARP inhibitor, olaparib (O), in metastatic castration-resistant prostate cancer (mCRPC). American Society of Clinical Oncology; 2017.
  5. Handy C, Baras AS, Lotan TL, Antonarakis ES. Prevalence of homologous recombination deficiency (HRD) mutations in localized prostate cancer according to Gleason grade: Implications for neoadjuvant clinical trial design. Journal of Clinical Oncology 2018; 36:5062-.
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