Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•The authors report on 3 cohorts of patients with metastatic castration-resistant prostate cancer treated with pembrolizumab in the phase II KEYNOTE-199 trial. The objective response rates (primary endpoint) in patients with PD-L1-positive and negative disease were 5% and 3%, respectively. The median duration of response was not reached and 10.6 months, respectively, while the median overall survival was 9.5 months and 7.9 months in the same groups.

•These findings show encouraging overall survival estimates and durability of responses achieved with pembrolizumab.

– Paul J. Hampel, MD

PURPOSE

Pembrolizumab has previously shown antitumor activity against programmed death ligand 1 (PD-L1)-positive metastatic castration-resistant prostate cancer (mCRPC). Here, we assessed the antitumor activity and safety of pembrolizumab in three parallel cohorts of a larger mCRPC population.

METHODS

The phase II KEYNOTE-199 study included three cohorts of patients with mCRPC treated with docetaxel and one or more targeted endocrine therapies. Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression. All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles. The primary end point was objective response rate per RECIST v1.1 assessed by central review in cohorts 1 and 2. Secondary end points included disease control rate, duration of response, overall survival (OS), and safety.

RESULTS

Two hundred fifty-eight patients were enrolled: 133 in cohort 1, 66 in cohort 2, and 59 in cohort 3. Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. Median duration of response was not reached (range, 1.9 to ≥ 21.8 months) and 10.6 months (range, 4.4 to 16.8 months), respectively. Disease control rate was 10% in cohort 1, 9% in cohort 2, and 22% in cohort 3. Median OS was 9.5 months in cohort 1, 7.9 months in cohort 2, and 14.1 months in cohort 3. Treatment-related adverse events occurred in 60% of patients, were of grade 3 to 5 severity in 15%, and led to discontinuation of treatment in 5%.

CONCLUSION

Pembrolizumab monotherapy shows antitumor activity with an acceptable safety profile in a subset of patients with RECIST-measurable and bone-predominant mCRPC previously treated with docetaxel and targeted endocrine therapy. Observed responses seem to be durable, and OS estimates are encouraging.

Journal of Clinical Oncology

Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study

J. Clin. Oncol 2019 Nov 27;[EPub Ahead of Print], ES Antonarakis, JM Piulats, M Gross-Goupil, J Goh, K Ojamaa, CJ Hoimes, U Vaishampayan, R Berger, A Sezer, T Alanko, R de Wit, C Li, A Omlin, G Procopio, S Fukasawa, KI Tabata, SH Park, S Feyerabend, CG Drake, H Wu, P Qiu, J Kim, C Poehlein, JS de Bono

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

[MateoBeach]

Objective response rates of 3% and 5% : Very low.

And OS of 9.5 and 7.1 months? Game over.

Was there no placebo/SOC arm? Perhaps in their larger population?

60% side effects with 15% grade 3 or more.

Not seeing much benefit. What am I missing?

[Claud68 in reply to MateoBeach]

They don't mention that pembrolizumab works only with the very uncommon gene MSI-hi and msh2 mutation, as it was found before?

[MateoBeach in reply to Claud68]

Thanks for that clarification , an important perspective.

[Vindog29]

My husband was found with gene mapping to have the rare Msh2 mutation and received 2 treatments of keytruda before his liver enzymes were elevated. His PSA became undetectable over first dose tumors shrunk and have stayed stable year later. He was Gleason 10,chemo,zytiga didnt work. From what I understand it is the rare Msh2 that prompted this response.

[MateoBeach in reply to Vindog29]

Happy to hear that he had such a great response. Hope it is durable. Amazing and dedicated science and so many generous trial participants to learn these specific rare gene variations in whom it works. Much is owed to them.

[Vindog29 in reply to MateoBeach]

Thank you for your kind words..I hope and pray one day EVERYONE will have a chance to experience a miracle