Can Merck overcome challenges in an immunologically “cold” tumour with Keytruda for prostate cancer?

GlobalData Healthcare 19th November 2019 (Last Updated November 22nd, 2019 09:36)

Prostate cancers are slow-moving tumours and are generally regarded as immunologically “cold”.

Can Merck overcome challenges in an immunologically “cold” tumour with Keytruda for prostate cancer?

Immuno-oncology represents a third major wave of strategies to treat cancer, after chemotherapy and targeted therapy. Some tumours, such as metastatic melanoma and advanced or metastatic non-small cell lung cancer (NSCLC) have seen great improvements with these treatments, however, other tumour types, such as prostate cancer, have lagged in this area. 

Prostate cancers are slow-moving tumours and are generally regarded as immunologically “cold”, with few immune cell-infiltrates to carry out immune recognition and cancer cell destruction after treatment with immune-stimulating agents. 

Prostate cancer

A new era of drug development has started in prostate cancer. Preliminary data, such as early readouts of the KEYNOTE-365 trial, have suggested an anti-tumour activity for immune checkpoint inhibitors in some patients with metastatic castration-resistant prostate cancer (mCRPC). 

Cohorts A and C have shown objective response rates between 13-20% for Keytruda when combined with other agents, which included AstraZeneca’s poly-ADP ribose polymerase (PARP)_ inhibitor, Lynparza, and Astellas/Pfizer’s Xtandi, respectively. 

This trend is typical for checkpoint inhibitors in other indications, where populations show low response rates but impressive survival for those who do respond. No survival data is available yet for Keytruda in prostate cancer patients. Four posters at SITC 2019 presented planned trials of Keytruda in prostate cancer, including three Phase III trials, and these are:

  • Pembrolizumab Plus Enzalutamide Versus Placebo Plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: Phase 3 KEYNOTE-641 Study
  • Pembrolizumab Plus Olaparib vs. Enzalutamide or Abiraterone Acetate in Patients with Metastatic Castration-Resistant Prostate Cancer Who Experienced Progression on Chemotherapy: Phase 3 KEYLYNK-101 Study
  • Pembrolizumab Plus Docetaxel and Prednisone for Enzalutamide- or Abiraterone Acetate – Pretreated Patients with Metastatic Castration-resistant Prostate Cancer: Phase 3 KEYNOTE-921 Study
  • KEYNOTE-365 Cohort D: Phase 1b/2 Study of Pembrolizumab Plus Abiraterone Acetate and Prednisone in Metastatic Castration-Resistant Prostate Cancer

The table below presents key criteria used in the designs of the four ongoing clinical trials of Keytruda, as shown in posters at SITC 2019. 

Based on these clinical trials, GlobalData expects Keytruda to be used as early as the first-line mCRPC and in three different combinations with Xtandi, Lynparza or docetaxel. 

Based on these three different uses, it is likely to outcompete Roche’s Tecentriq, which is also eyeing prostate cancer for second-line usage in combination with Xtandi. GlobalData forecasts Keytruda sales at $585m in 2028, compared with Tecentriq’s $155m. 

Although KOLs interviewed by GlobalData were eager for more options to treat prostate cancer, including new mechanisms of action, there is very little data to suggest that checkpoint inhibitors are effective in this disease. Interviewed experts pointed out that prostate cancer is a “cold tumour”, suggesting that it may instead benefit from a combination strategy that increases immune infiltrates in the tumour.

One KOL did suggest that PD-L1 could be overexpressed in response to Xtandi treatment, as this was shown in a small cohort of patients treated with the drug and in a preclinical mouse model. This could mechanistically support the use of Keytruda for prostate cancer, at least in combination with second-generation hormone agents such as Xtandi. Beyond questions over the drug’s rationale for prostate cancer, KOLs had further concerns over its toxicity. However, with three robust Phase III clinical trials in prostate cancer, clinicians should soon have an answer to questions over the efficacy of immune checkpoint inhibitors in prostate cancer with well-controlled, international, randomized clinical trials.

Related reports

GlobalData (2020). Immuno-oncology Thematic Report, to be published

GlobalData (2018). Immuno-oncology Development Trends and Opportunities, GDHCHT015, November 2018

GlobalData (2019). Prostate Cancer: Global Drug Forecast and Market Analysis to 2028, GDHC162PIDR, August 2019

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