Three Keytruda Combinations Show Signs of Efficacy in Metastatic CRPC

Combining the immune checkpoint inhibitor Keytruda (pembrolizumab) with either a PARP inhibitor, chemotherapy, or hormone therapy led to promising signs of activity in metastatic castration-resistant prostate cancer (mCRPC) patients in a Phase 1b/2 trial, Merck — Keytruda’s developer — announced.

The findings were presented at the 2019 Genitourinary Cancers Symposium (ASCO GU), Feb. 14-16 in San Francisco, California.

Keytruda, by Merck (MSD outside the U.S. and Canada), binds to the PD-1 receptor on immune cells and prevents the binding of the PD-L1 ligand produced by cancer cells. Cancer cells use this mechanism to evade immune surveillance, and thus, Keytruda is meant to restore a functional immune system that effectively fights cancer.

The KEYNOTE-365 Phase 1b/2 trial (NCT02861573) — still looking for participants — was designed to test multiple Keytruda combinations for the treatment of men with metastatic castration-resistant prostate cancer.

The trial has four arms, or cohorts, receiving Keytruda in combination with another therapy:

Cohort A: The PARP inhibitor Lynparza (olaparib);

Cohort B: The chemotherapy docetaxel and prednisone;

Cohort C: The hormone therapy Xtandi (enzalutamide);

Cohort D: Zytiga (abiraterone acetate) and prednisone.

It is designed to determine the combinations’ safety, overall response rates, and PSA response rate (deemed as a 50% or greater reduction in PSA levels) as primary measures. Secondary endpoints include disease control rate, time to disease progression on radiographic scans or death, and overall survival.

At the 2019 ASCO GU, researchers presented interim efficacy and safety findings from cohorts A, B and C.

Cohort A: “Keynote-365 cohort a: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).”

Cohort A enrolled 41 patients who had received prior docetaxel chemotherapy, up to one additional chemotherapy, and up to two second-generation hormone therapies. They received Keytruda (every three weeks), along with oral Lynparza (given as 400 mg capsules twice daily).

After a median follow-up of 11 months, 12% of patients showed a PSA response — those with measurable disease had a response rate of 14%; those with non-measurable disease, 8%.

The median time to PSA progression was 15.3 and 18.1 weeks for patients with measurable and non-measurable disease, respectively. A partial response was also seen in 2 of 28 patients (7%) with measurable disease.

Overall, 29% of patients achieved at least disease stabilization (lasting six months or more), and lived on average 4.7 months without radiographic signs of disease progression. Median overall survival was 13.5 months and 73% of the patients were alive after six months.

Serious treatment-related adverse events were detected in 49% of patients, the most common being  anemia. One patient died because of treatment-related adverse events.

Cohort B: “Keynote-365 cohort b: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC).”

Cohort B enrolled 72 patients previously treated with Zytiga or Xtandi who had not yet received any chemotherapy regimen. They were given Keytruda plus the chemotherapy docetaxel (75 mg) and the immunosuppressant prednisone (5 mg) orally twice daily.

PSA responses were observed in 31% of patients — 22% and 39% of patients with measurable disease and non-measurable disease, respectively.

Median time to PSA progression was 24.1 and 30.4 weeks for each group of patients (measurable and non-measurable disease). Those with measurable disease showed a partial response rate of 14%, and the median duration of response was 4.9 months.

Disease control rate (by six months or more) was achieved by 57% of patients. Patients lived on average 8.3 months without radiographic signs of disease progression — by six months, 79% remained progression-free. After six months, 96% of patients remained alive.

Serious treatment-related adverse events were detected in 36% of patients, the most common being febrile neutropenia — when fever occurs in patients with a low number of immune cells, called neutrophils. Two patients died because of pneumonitis.

Cohort C – “Keynote-365 cohort C: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate resistant prostate cancer (mCRPC).

Cohort C enrolled 69 patients who received prior Zytiga but no chemotherapy regimen. They received Keytruda along with oral Xtandi (160 mg per day).

Overall, 26% of patients had a PSA response — those with measurable disease had a response rate of 40%; those with non-measurable disease, 18%.

The median time to PSA progression was 18.4 and 12.4 weeks for patients with measurable and non-measurable disease, respectively. Responses were observed in 20% of patients, including 8% complete responses.

Disease control rate (by six months or more) was achieved by 33% of patients. Median duration of response was 8.3 months, with 75% of patients having responses lasting longer than six months.

The median time to radiological disease progression or death was 6.1 months. More than half of the patients were still alive at the time of the analysis. At six months, the overall survival rate was 91%.

Serious treatment-related adverse events were detected in 41% of patients, the most common being rash. No patient died of treatment-related adverse events.

“At the core of our research program is a commitment to investigate the potential of Keytruda — both as combination and monotherapy — to serve as a foundational treatment, especially for cancers where additional therapies are needed,” Roy Baynes, senior vice president, head of global clinical development, and chief medical officer, Merck Research Laboratories, said in a press release.

“These promising data presented at ASCO GU, coupled with the significant unmet medical need in patients with metastatic castration-resistant prostate cancer, propelled us to initiate three new Phase 3 trials to further evaluate these Keytruda combination regimens,” he said.

Hence, Merck is expanding its cancer immunotherapy program for mCRPC and is launching three new Phase 3 trials testing a combination of:

Keytruda and Lynparza — KEYLYNK-010 (NCT03834519);

Keytruda plus docetaxel and prednisone — KEYNOTE-921 (NCT03834506);

Keytruda and Xtandi — KEYNOTE-641 (NCT03834493).