PD-1 inhibitor shows some antitumor activity in prostate cancer

With additional follow-up of approximately 10 months, monotherapy with the PD-1 inhibitor pembrolizumab (Keytruda) continued to show antitumor activity in men with metastatic castration-resistant prostate cancer (mCRPC). However, monotherapy alone is likely not a sufficient treatment in this patient population, according to Emmanuel Antonarakis, MBBCh, professor of oncology at Johns Hopkins University in Baltimore, Maryland.

Antonarakis presented findings on cohorts 1 to 3 of the multicohort KEYNOTE-199 study (NCT02787005) at the Genitourinary Cancers Symposium in San Francisco. A previous analysis showed that pembrolizumab alone has antitumor activity and acceptable safety in patients with mCRPC who were previously treated with a next-generation hormonal agent and docetaxel. In this interview by Urology Times^®’ sister publication OncologyLive^®, Antonarakis discusses updated results with additional follow-up in this population.

Q: Can you give a little background on KEYNOTE-199 and the rationale for this study?

A: What we presented this year at the 2020 Genitourinary Cancers Symposium was an updated analysis of the KEYNOTE-199 pembrolizumab study in advanced prostate cancer. This is a study of single-agent pembrolizumab in 5 different cohorts. The first 3 cohorts were without the use of enzalutamide [Xtandi]. Then cohorts 4 and 5, which were presented at the symposium by Julie Graff, MD [Oregon Health & Science University], were looking at the patients progressing on enzalutamide where the pembrolizumab was added in conjunction with enzalutamide.

This was sort of an encore presentation; we have previously published results in the Journal of Clinical Oncology of the first 3 cohorts of the study.

Q: What were the key findings?

A: The first 3 cohorts were people who were receiving pembrolizumab as a monotherapy in 1 of 3 groups. First were patients who had soft tissue disease and were PD-L1 positive by immunohistochemistry. The second group consisted of patients with soft tissue disease who were PD-L1 negative. And the third group consisted of patients who had bone-predominant or bone-only metastases.

The punchline of the encore abstract is that it’s very consistent with the original data from the Journal of Clinical Oncology publication. We have an additional 10 or 11 months of median follow-up, so we have more mature follow-up, but the message is fairly consistent. We’re seeing about a 4% or 5% objective response rate in these patients with pembrolizumab monotherapy. Again, this is a CRPC [castration-resistant prostate cancer] population, and we’re seeing approximately a 10% PSA [prostate specific antigen] response rate.

The safety seems consistent. There doesn’t seem to be any extra or negative safety signal for our patients to be concerned about, with the main side effect being fatigue. The risk of autoimmune conditions when pembrolizumab is used as a monotherapy in prostate cancer is quite low, so we don’t have to worry too much about that.

Overall, this suggests that there is some activity with pembrolizumab as a monotherapy, but we need to do better. This leads to the next phase of the development of this drug, which will be in combination with either enzalutamide, and there’s an ongoing phase 3 study; or in combination with docetaxel, and there’s another ongoing phase 3 study for that; or in combination with the PARP inhibitor olaparib, and there’s also a phase 3 study with that. So, I think as a monotherapy, it’s been encouraging but probably not enough on its own. And now we need to figure out what’s the best combination partner and there might be more than 1.

Q: What other take-home messages from these data do you have for clinicians?

A: In a biomarker-unselected population, any PD-1 or PD-L1 inhibitor by itself is probably not going to be enough. Now, there are some patients [for whom] even as a monotherapy, a PD-1 or a PD-L1 inhibitor might be beneficial, for example, the small subset of patients who have mismatch repair deficiency or microsatellite instability high genotypes. The second population [for whom] these drugs might work as monotherapy could be those patients who have CDK12 mutations.

And then there are some preliminary data that have not yet been confirmed [indicating] that perhaps patients…with BRCA2 and BRCA1 mutations may also be slightly enriched for a response to single-agent PD-1 blockers.

Disclosure: Merck provided funding for the study. For full disclosures from Antonarakis and study co-authors, see https://bit.ly/2yhAWzK.