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by Kristin Jenkins, Contributing Writer, MedPage Today
December 10, 2019
Pembrolizumab (Keytruda) monotherapy demonstrated antitumor activity with manageable safety in a small subgroup of men with previously treated metastatic castrate-resistant prostate cancer (mCRPC), researchers found.
Results from the first three cohorts in the five-cohort phase II, open-label, multi-center KEYNOTE-199 trial showed a combined overall response rate to pembrolizumab monotherapy in nine patients (5%) out of 199 in cohorts 1 and 2 combined. The combined median duration of response was 16.8 months, said Johann Sebastian de Bono, MD, PhD, of the Institute of Cancer Research and the Royal Marsden Hospital in London, and colleagues.
An ongoing response was observed in five patients at data cutoff with four responders remaining on treatment after 21.8 months, they reported in the Journal of Clinical Oncology.
"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 authors wrote.
In a statement, de Bono said the current study shows that "super responders" could live for 2 years or even longer. "We don't see much activity from the immune system in prostate tumors, so many oncologists thought immunotherapy wouldn't work for this cancer type. But our study shows that a small proportion of men with end-stage cancer do respond and ... that some of these men do very well indeed."
Patients with DNA repair mutations appeared to respond particularly well to immunotherapy, said de Bono, who added that two of his own patients have been on pembrolizumab for more than 2 years. Local biomarker testing by immunohistochemistry revealed a mismatch repair defect that was below the cutoff for high microsatellite instability by mSINGS assay.
W. Kevin Kelly, DO, of the Sidney Kimmel Cancer Center-Jefferson Health in Philadelphia, emphasized that in prostate cancer, the dilemma of how to identify patients who will respond to immunotherapy remains.
"This is interesting work, but there is no clear cut reason why some patients respond or not," Kelly told MedPage Today. "Much more work needs to be done to identify biomarkers."
Although the study showed clinical activity in a small subset of patients, whether this immune therapy will extend overall survival (OS) in the general prostate cancer population remains unclear, added Kelly, who was not involved in the study. "This [study] is not going to change the standard of care," he stressed.
Kelly also pointed out that treatment-related adverse events (TRAEs) of grades 3 to 5 were seen in 15% of patients. "We have to be respectful of that."
In the study, 29% of patients had previously undergone two or more chemotherapy regimens, and about 25% were treated with both enzalutamide (Xtandi) and abiraterone (Zytiga).
In cohort 1, which was comprised of PD-L1-positive patients, one patient out of 133 with mCRPC achieved a complete radiologic response to pembrolizumab 200 mg administered intravenously every 3 weeks for a maximum of 35 cycles. Five patients had a partial response. In cohort 2, those with PD-L1-negative disease, two patients out of 65 achieved partial responses.
Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. The latter was made up of 59 men with bone-predominant disease, regardless of PD-L1 status.
"Observed responses seem to be durable, and observed OS estimates are promising, suggesting that immunotherapy may be able to extend the tail of the survival curve in a historically difficult-to-treat population," the authors wrote.
In 243 patients assessed for baseline prostate-specific antigen (PSA), 9% had a decrease in PSA level of ≥50% and 5% had a ≥90% decrease. At baseline, the median PSA level was 115.5 ng/mL in cohort 1, 116.1 ng/mL in cohort 2, and 43.3 ng/mL in cohort 3.
In 153 of 258 patients across all three cohorts, including six of nine with complete or partial response, whole-exome sequencing of tumor samples showed that 19 patients (12%) had germline mutations in BRCA1/2 or ATM genes and that 10 patients (7%) had aberrations in one or more of 12 other homologous recombination repair genes. "Prospective trials would be required to assess the relationship between DNA repair defects of interest and antitumor activity," the investigators said.
Pending data from cohorts 4 and 5 of KEYNOTE-199 will help determine whether pembrolizumab monotherapy has activity in patients with chemotherapy-naive mCRPC receiving ongoing enzalutamide treatment, they predicted. "Ongoing and future biomarker studies from KEYNOTE-199, including exploration of different [combined positive score] cut points, gene expression profiles, and tumor mutational burden, will aim to uncover molecular markers of response to single-agent pembrolizumab."
Other studies involving PD-1 inhibitor-based combination regimens have shown activity in mCRPC, including the CheckMate 650 trial of nivolumab (Opdivo) plus the CTLA-4 checkpoint inhibitor ipilimumab (Yervoy) and KEYNOTE-365, which showed promising antitumor activity and well-tolerated TRAEs when pembrolizumab was combined with olaparib (Lynparza), docetaxel, and enzalutamide.
KEYNOTE-199 was funded by Merck, Sharp & Dohme (MSD).
de Bono disclosed relevant relationships with MSD, AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech, Janssen Oncology, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, Bioexcell, Bayer, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Celgene, Taiho Pharmaceutical, Genmab, GlaxoSmithKline, Eisai, BioXCel Therapeutics, Taiho Pharmaceutical, Orion Pharma, CellCentric, MedImmune, Medivation, Qiagen, and Vertex. Co-authors disclosed multiple relevant relationships with industry."
Immunotherapy (general) - Interesting NY Times Article.
Effects of Metformin and Statins on MCRPC
Bone Marrow Transplant for MCRPC
Immunotherapy for prostate cancer continues to disappoint, but at least we are learning why
