Keytruda Shows Promise for Some with Highly Advanced Prostate Cancer in Phase 2 Trial

Keytruda Shows Promise for Some with Highly Advanced Prostate Cancer in Phase 2 Trial

The immunotherapy Keytruda (pembrolizumab) extended for at least two years the lives of a small proportion of men with metastatic castration-resistant prostate cancer (mCRPC) who had exhausted all other treatment options, data from a Phase 2 trial show.

While no association was seen between PD-L1 status and treatment responses, some of the men carried mutations in genes involved in DNA repair. These mutations will now be evaluated as potential predictive biomarkers to identify patients who are more likely to benefit from Keytruda.

The study, “Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study,” was published in the Journal of Clinical Oncology.

Keytruda, an immune checkpoint inhibitor marketed by Merck (known as MSD outside the U.S. and Canada), suppresses a mechanism often used by cancer cells to evade anti-tumor immune responses. By preventing the interaction between the PD-1 receptor in immune T-cells and its ligand PD-L1 in cancer cells, Keytruda boosts T-cells’ ability to detect and fight tumor cells.

Because it targets the PD-1/PD-L1 interaction, patients with higher levels of PD-L1 on their tumor often respond better to Keytruda and similar  immune checkpoint inhibitors.

The international KEYNOTE-199 Phase 2 trial (NCT02787005) evaluated the safety and effectiveness of Keytruda in 258 mCRPC patients who had acquired resistance to docetaxel chemotherapy and androgen deprivation therapy (ADT).

The study comprised three groups of patients. Group 1 had 133 men with PD-L1 positive tumors (meaning their tumors expressed PD-L1, the protein to which PD-1 on immune cells binds to), group 2 included 66 men with PD-L1 negative tumors, and group 3 had 59 men with bone-predominant disease, regardless of PD-L1 status. Participants’ median age was 68, and they received 200 mg of Keytruda every three weeks for up to 35 cycles (approximately two years).

The trial’s main goal was the proportion of patients who responded to treatment — defined as at least a 30% reduction in tumor size — in groups 1 and 2. Secondary goals included disease control rate (the proportion of patients who achieved at least disease stabilization), duration of response, overall survival, and safety in all groups.

Results showed that tumors in 5% of patients in groups 1 and 2 reduced in size or disappeared — 5% in the PD-L1 positive group, and 3% in the PD-L1 negative group. Median duration of response had not been reached for group 1, meaning that most patients where still responding, those in group 2 showed a median response of 10.6 months.

Disease stabilization was observed in similar proportions in groups 1 and 2 (10% and 9%, respectively), but at a higher proportion (22%) among patients with bone metastases (group 3). Men in group 3 also lived longer (median of 14.1 months) than those with stabilized disease in the other two groups (9.5 months in group 1, and 7.9 months in group 2).

These data highlighted that PD-L1 status could not predict which patients would respond better to treatment, and that patients whose disease has spread to the bone may benefit from Keytruda.

While the number of men responding to Keytruda was small — with 1 in every 20 showing a significant benefit — the researchers noted that their responses were surprisingly durable.

Of the nine men achieving a complete or partial response (from groups 1 and 2), four were considered “super responders,” as they were still on treatment at the end of study follow-up, and showed responses lasting at least 22 months (about two years).

“Our study has shown that a small proportion of men with very advanced prostate cancer are super responders to immunotherapy and could live for at least two years and possibly considerably longer,” Johann de Bono, a KEYNOTE-199’s clinical investigator, said in a press release. de Bono is also a regius professor of cancer research at The Institute of Cancer Research (ICR), in London, and a consultant medical oncologist at The Royal Marsden NHS Foundation Trust.

While researchers are still working to identify factors that determine the therapy’s success in this small group of patients, genetic analyses of tumors from six responders found that four of them had mutations in DNA repair genes.

“We found that men with mutations in DNA repair genes respond especially well to immunotherapy, including two of my own patients who have now been on the drug for more than two years. I am now leading a larger-scale trial specifically for this group of patients and am excited to see the results,” said de Bono.

The team plans to evaluate whether these mutations can appropriately stratify which patients are likely to respond to Keytruda and which are likely to not.

“It’s encouraging to see testing for DNA repair mutations may identify some patients who are more likely to respond, and I’m keen to see how the new, larger trial in this group of patients plays out,” said Paul Workman, ICR’s chief executive.

Keytruda was well-tolerated, with a safety profile consistent with that reported in previous trials. Treatment-related adverse events were reported by 60% of patients, were serious to life-threatening in 15% of them, and led to treatment discontinuation in 5%.