Julie N. Graff, MD, associate professor of medicine, Oregon Health & Science University Knight Cancer Institute, discusses combination regimens with checkpoint inhibitors in metastatic castration-resistant prostate cancer (mCRPC).

Historically, single-agent checkpoint inhibitors have not elicited significant survival benefits in patients with mCRPC, explains Graff. However, higher response rates have been noted with combination therapies.

The phase 1b/2 KEYNOTE-365 trial evaluated the efficacy of pembrolizumab (Keytruda) plus the PARP inhibitor olaparib (Lynparza), and pembrolizumab plus docetaxel and prednisone, says Graff.

Additional combinations of interest include PD-1 inhibitors plus CLTA-4 inhibitors, concludes Graff.

Videos

Julie N. Graff, MD, discusses potential combination regimens with checkpoint inhibitors in metastatic castration-resistant prostate cancer.

Dr. Graff on Combination Regimens With Checkpoint Inhibitors in mCRPC

Julie N. Graff, MD, associate professor of medicine, Oregon Health & Science University Knight Cancer Institute, discusses the phase III KEYNOTE-641 trial in metastatic castration-resistant prostate cancer (mCRPC).

At the 2020 Genitourinary Cancers Symposium, data from cohorts 4 and 5 of the phase II KEYNOTE-199 trial demonstrated that the addition of pembrolizumab (Keytruda) to enzalutamide (Xtandi) resulted in moderate activity in patients with chemotherapy-naïve mCRPC who progressed on enzalutamide.

Accordingly, Merck has launched the phase III KEYNOTE-641 trial, in which patients with mCRPC will be randomized to receive either enzalutamide plus placebo or enzalutamide plus pembrolizumab to determine whether the addition of pembrolizumab extends overall survival, concludes Graff.

Dr. Graff on the KEYNOTE-641 Trial in mCRPC

Julie N. Graff, MD, associate professor of medicine, Oregon Health & Science University Knight Cancer Institute, discusses the safety profile of pembrolizumab (Keytruda) plus enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Now that checkpoint inhibitors are approved for use in several disease states, the risks with these agents are becoming more well-known, explains Graff. The combination of enzalutamide and pembrolizumab, or any PD-1 inhibitor, appears to result in more rashes for patients with mCRPC, says Graff.

Results of the KETNOTE-199 trial, in which patients with mCRPC received pembrolizumab plus enzalutamide, showed that 25% of patients developed a rash. Of those cases, only 1 was grade 3 and required intravenous steroids. The rest of the patients were managed with topical or oral steroids. Otherwise, the safety profile of pembrolizumab plus enzalutamide was as expected, concludes Graff.

Julie N. Graff, MD, discusses the safety profile of pembrolizumab plus enzalutamide in patients with metastatic castration-resistant prostate cancer.

Dr. Graff on the Safety of Checkpoint Inhibition in mCRPC

Julie N. Graff, MD, associate professor of medicine, Oregon Health & Science University Knight Cancer Institute, discusses the results of the phase II KEYNOTE-199 trial in metastatic castration-resistant prostate cancer (mCRPC).

At the 2020 Genitourinary Cancers Symposium, findings from cohort 4 (n = 81) and cohort 5 (n = 45) of the KEYNOTE-199 trial were presented. In both cohorts, patients with enzalutamide (Xtandi)-resistant mCRPC received the combination of pembrolizumab (Keytruda) and enzalutamide (Xtandi). Notably, cohort 4 consisted of patients with measurable RECIST mCRPC, whereas cohort 5 enrolled patients with nonmeasurable RECIST bone-only/bone-predominant mCRPC.

A 12% overall response rate defined as ≥30% reduction in tumor size was reported in cohort 4. The disease-control rate (DCR) was 51%, and the duration of response was 6.3 months. The DCR in cohort 5 was 51%.

Radiographic progression-free survival was 4.2 months in cohort 4 and 4.4 months in cohort 5. Overall survival was not reached in cohort 4 and was 18.8 months in cohort 5.

Overall, 40% of patients had a prostate-specific antigen (PSA) decline from baseline. Notably, 14% of patients experienced a PSA decline ≥50%.

The combination is currently being evaluated in the phase III KEYNOTE-641 trial.

Julie N. Graff, MD, discusses the results of the phase II KEYNOTE-199 trial in metastatic castration-resistant prostate cancer.

Dr. Graff on Results of the KEYNOTE-199 Trial in mCRPC

Julie N. Graff, MD, associate professor of medicine, Oregon Health & Science University Knight Cancer Institute, discusses the multi-cohort, phase II KEYNOTE-199 study examining patients with metastatic castration-resistant prostate cancer (mCRPC).

The current standard of care for patients with mCRPC varies from place to place, explains Graff. Typically, chemotherapy is available to patients and some providers would consider giving abiraterone acetate (Zytiga) after enzalutamide (Xtandi). This regimen provides some responses in the later-line setting, though not as many when it is given upfront, according to Graff.

Cohorts 1, 2, and 3 in the KEYNOTE-199 involved men with CRPC who received single-agent pembrolizumab (Keytruda) after chemotherapy and next-generation androgen receptor inhibitors. Cohorts 4 and 5 were men with mCRPC prior to chemotherapy who had progressed on enzalutamide after showing a response. Cohort 4 contained patients with measurable disease while cohort 5 comprised patients without measurable disease. Patients continued on enzalutamide and received pembrolizumab every 3 weeks until intolerance or progression, concludes Graff.

Julie N. Graff, MD, discusses the multi-cohort, phase II KEYNOTE-199 study examining patients with metastatic castration-resistant prostate cancer.

Dr. Graff on the KEYNOTE-199 Trial Design in Castration-Resistant Prostate Cancer

Julie N. Graff, MD, assistant professor of medicine, OHSU Knight Cancer Institute, discusses treatment for patients with high-risk metastatic disease following the FDA approval of abiraterone acetate (Zytiga).

Phase III results from the LATITUDE trial led to the approval of abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic hormone-naïve prostate cancer.

In high-risk patients, Graff advises physicians use, or at least offer, abiraterone in newly diagnosed metastatic disease. Physicians now know that men who are high risk with visceral disease, many bone metastases, and high Gleason scores can live longer with early use of abiraterone.

Graff notes that it may not be the standard of care for these patients. Although there are no direct studies comparing the use of abiraterone to the use of chemotherapy, Graff states that chemotherapy may be a better alternative for these patients. There’s a financial incentive for patients because chemotherapy is comparatively cheaper to abiraterone. Also, chemotherapy has a shorter and more defined regimen, whereas abiraterone is given until the cancer progresses.

Julie N. Graff, MD

Articles

Dr. Graff on Combination Regimens With Checkpoint Inhibitors in mCRPC

Dr. Graff on the KEYNOTE-641 Trial in mCRPC

Dr. Graff on the Safety of Checkpoint Inhibition in mCRPC

Dr. Graff on Results of the KEYNOTE-199 Trial in mCRPC

Dr. Graff on the KEYNOTE-199 Trial Design in Castration-Resistant Prostate Cancer

Dr. Graff on the Use of Abiraterone in Metastatic Prostate Cancer