Pembrolizumab Shows Limited Activity Against Prostate Cancer

By Will Boggs MD

December 06, 2019

NEW YORK (Reuters Health) - Pembrolizumab shows limited activity in selected men with treatment-refractory metastatic castration-resistant prostate cancer (mCRPC), according to findings from the open-label KEYNOTE-199 study.

In a recent study of 23 men with PD-L1-positive mCRPC, the anti-PD-1 monoclonal antibody pembrolizumab provided a 17% objective-response rate (ORR), a 30% disease-control rate (DCR), and a 37% estimated 12-month overall-survival rate.

Dr. Johann Sebastian de Bono from The Institute of Cancer Research And Royal Marsden Hospital, in London, and colleagues further explored the antitumor activity and safety of pembrolizumab in their study of men who previously received docetaxel and targeted endocrine therapy. The patients had disease that was measurable and PD-L1 positive (cohort 1, 133 patients) or negative (cohort 2, 68 patients) or that was bone-predominant, regardless of PD-L1 status (cohort 3, 59 patients).

The ORR, the primary endpoint, was 5% in cohort 1, 3% in cohort 2, and 5% in cohorts 1 and 2 combined, the researchers report in the Journal of Clinical Oncology.

DCR was 13% in cohort 1, 18% in cohort 2, 39% in cohort 3, 15% in cohorts 1 and 2 combined, and 20% in all 3 cohorts combined.

Median response duration was not reached in cohort 1 (range, 1.9 to at least 21.8 months). It was 10.6 months in cohort 2 and 16.8 months in cohorts 1 and 2 combined.

Median radiographic progression-free survival was 2.1 months in cohorts 1 and 2 and 3.7 months in cohort 3. Median overall survival was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3, with estimated 12-month survival rates of 41%, 35%, and 62%, respectively.

In exploratory biomarker analyses, ORR was 11% in men with BRCA1/2 or ATM aberrations, 0% in men with aberrations in one or more of the other 12 homologous recombination repair (HRR) genes analyzed, and 3% in men without any HRR gene aberrations.

Overall, 60% of patients experienced one or more treatment-related adverse events, including 15% with one or more grade-3 to -5 treatment-related adverse events and 5% who discontinued pembrolizumab because of a treatment-related adverse event.

Immune-mediated adverse events occurred in 16% of patients and led to discontinuation in 2% of patients and death in one patient.

"These data add to the growing body of evidence that suggests that, despite its more immunosuppressive microenvironment, a small number of select patients with mCRPC may benefit from pembrolizumab," the researchers conclude.

Dr. Marlena Janiczek of Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, in Torun, Poland, who recently reviewed immunotherapy as a treatment for prostate cancer, told Reuters Health by email, "As highlighted aptly at the end of the article, this study has several limitations, including no randomization, no control arm, and relatively short follow-up. In addition, the treatment of patients with hormonal therapy prior to pembrolizumab administration was not the same, which also makes it difficult to define the relevant findings."

"Conclusions about the evident beneficial effects of pembrolizumab in bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy are also incomplete, as only some patients provided biopsy samples that can be subjected to entire exome DNA sequencing," she said. "Therefore, the genetic picture could not be fully characterized and molecular markers of response to pembrolizumab could not be identified."

Dr. Janiczek called for further research to define the role, if any, of pembrolizumab treatment in mCRPC. "The study only indicates that the group of patients with bone-predominant mCRPC should be looked at the most," she added.

Dr. de Bono did not respond to a request for comments.

Merck Sharp and Dohme funded the study and employed or had other financial ties to nearly all the authors.

SOURCE: https://bit.ly/33SBOEK Journal of Clinical Oncology, online November 27, 2019.

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