Olaparib/Pembrolizumab Combo Continues to Show Promising Activity in mCRPC

Author(s):

The combination of olaparib and pembrolizumab continued to demonstrate antitumor activity in patients with metastatic castration-resistant prostate cancer who previously received docetaxel.

Luke T. Nordquist, MD, FACP

The combination of olaparib (Lynparza) and pembrolizumab (Keytruda) continued to demonstrate antitumor activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel, according to updated data from the ongoing phase 1b/2 KEYNOTE-365 trial presented during the 2021 AUA Annual Meeting.¹

“With a minimum of 11.4 months follow-up, pembrolizumab plus olaparib demonstrated antitumor activity and an acceptable safety profile for men with molecularly unselected, docetaxel-pretreated mCRPC,” said author Luke T. Nordquist, MD, FACP, medical oncologist and CEO of the Urology Cancer Center & GU Research Network, Omaha, Nebraska.

The KEYNOTE-365 trial (NCT02861573) was launched to assess the efficacy and safety of the olaparib/pembrolizumab regimen in patients with mCRPC. Prior results shared from cohort A showed promising clinical activity in molecularly unselected patients who had previously received docetaxel.^2,3

In the study, at a mean follow-up of 19.3 months (range, 11.4-45.9), patients received 200 mg of pembrolizumab intravenously every 3 weeks and 400 mg or 300 mg of olaparib orally twice daily, until disease progression, unacceptable toxicity, or withdrawal of consent. Standard bone scanning, CT, or MRI were also performed every 9 weeks for 54 weeks, and then every 12 weeks until disease progression. Primary end points were prostate-specific antigen (PSA) response rate, objective response rate determined by RECIST v1.1 through a blinded independent central review, and safety. Secondary end points included time to PSA progression, disease control rate, duration of response, radiographic progression-free survival, and overall survival.

“Cohort A of KEYNOTE-365 examined specifically the safety and efficacy of the combination of pembrolizumab and olaparib in molecularly unselected patients with mCRPC,” Nordquist said.

Patients were enrolled if they had molecularly unselected, docetaxel-pretreated mCRPC that had progressed within 6 months of screening. They also must have been treated previously no more than once with chemotherapy for mCRPC and no more than twice with second-generation hormonal therapies.

Of the 104 patients who enrolled, 102 were treated and 92 discontinued their treatment, mainly due to the progression of their disease (51%). Median age of enrolled patients was 69.5 years (range, 47-84), 29 patients (28.4%) were PD-L1 positive, 34 (33.3%) had visceral disease, and 58 (56.9%) had measurable disease. Twenty-four patients (23.5%) had previously been treated with abiraterone (Zytiga) only, 24 (23.5%) had previously been treated with enzalutamide (Xtandi) only, and 46 patients (45.1%) had previously been treated with both.

PSA response rate in all patients with a PSA measurement at baseline (n = 102) was 14.7% (95% CI, 8.5-23.1) and in the 58 pts who had measurable disease, confirmed objective response rate was 6.9% (95% CI, 1.9-16.7; 4 partial responses).

“The overall disease control rate was 26% for the total population, and clinical activity was consistent across PD-L1 and HR mutation subgroups,” Nordquist said.

Additionally, investigators found the median time to PSA progression was 4 months (range, 3.0-4.9 months), the median duration of response was not reached (range, 7.2+ to 37.8+ months), the disease control rate was 26.5% (95% CI, 18.2-36.1), the median radiographic progression-free survival was 5.2 months (range, 4.1-6.5) and the median overall survival was 14.4 months (range, 10.4-17.9).

There were high rates of treatment-related adverse events (TRAEs), which occurred in 93 patients (91.2%). The most frequent AEs (≥30%) were anemia (41.2%), nausea (41.2%), decreased appetite (30.4%), and fatigue (30.4%). A smaller, but significant rate of grade 3-5 TRAEs occurred in 49 patients (48.0%). Six patients (5.9%) died of AEs and 2 deaths were treatment related.

“The safety profile of pembrolizumab plus olaparib in combination is consistent with individual profiles of each agent. These results do support further evaluation of this combination in mCRPC,” concluded Norquist.

The phase 3 KEYLYNK-010 trial (NCT03834519) will further investigate pembrolizumab plus olaparib by comparing their efficacy vs abiraterone or enzalutamide in abiraterone- or enzalutamide-pretreated patients with mCRPC who have experienced disease progression on or after docetaxel for mCRPC.

References

Nordquist LT, Yu EY, Piulats JM, et al. Pembrolizumab (Pembro) plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC): updated results from KEYNOTE-365 cohort A with a minimum of 11 months of follow-up for all patients. Paper presented at the 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP24-14
Yu EY, Piulats JM, Gravis G, et al. KEYNOTE-365 cohort A updated results: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol 2020;38(suppl 6):100. doi:10.1200/JCO.2020.38.6_suppl.100
Yu EY, Massard C, Retz M, et al. Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol 2019;37(suppl 7):145. doi:10.1200/JCO.2019.37.7_suppl.145