Immunotherapy promising treatment option for metastatic castrate-resistant prostate cancer

Immunotherapy, in the setting of advanced prostate cancer (PCa), may alter the poor prognosis  of advanced PCa into a chronic disease with significantly longer overall survival , says an expert.

Dr Lukman Hakim, of the Department of Urology, Airlangga University, Surabaya, Indonesia, said some cases of PCa can progress to a metastatic castrate-resistant stage with short OS. Current treatment strategies are yet to be optimized, and multiple methods are being utilized to find the optimum way to prolong survival.

Immunotherapy is a suitable candidate in the treatment of PCa as the cancer affects its microenvironment, which leads to suppression of immune response thus leading to its escape from immune destruction. PCa is also characterized by slow growth kinetics and highly differentiated ?(sounds hanging…differentiated ?form). This variability offers a range of antigen targets, namely prostate-specific antigen (PSA), prostate-specific membrane antigen (PSMA), prostatic acid phosphatase (PAP) and prostate stem cell antigen (PSCA). [https://doi.org/10.2217/imt.15.101 Accessed on 28 August]

Currently, PCa is ‘curable’ when diagnosed at an early stage and treated while still localized. Unfortunately, some still progress to metastatic castrate-resistant prostate cancer (mCRPC), has very poor prognosis Existing approved treatment options for mCRPC can only prolong survival by 2.4 to 4.8 months.

Current research suggests immunotherapy in advanced PCa is a viable option to alter the often-dismal prognosis to one which is more chronic in nature, by achievement of significantly improved survival. Recent clinical trials involving PCa are focused on strategies as diverse as sequencing, combination therapy, and immunotherapy.  

Lukman noted that the tumour microenvironment characteristic of PCa, which plays an important role in the immune system, is not fully understood and requires further elucidation. One of the reasons there have been limited results in the treatment of metastatic disease, is the immunosuppressive mechanisms exerted by the tumour. So far, the only immunotherapy approved for PCa treatment is sipuleucel-T.

There is hope on the horizon, however, as many vaccines, monoclonal antibodies (checkpoint inhibitors), chimeric antigen receptor (CAR) T-cells and tumour microenvironment disruptors are currently showing promising results in trials. In the case of vaccines, personalized peptide vaccination (PPV) in patients with CRPC are showing benefit in terms of survival. [Int J Urol 2017;24(9):675–680]

The checkpoint inhibitor pembrolizumab is currently being tested in the KEYNOTE-028 and KEYNOTE-199 trials. Early results suggest that a small but meaningful proportion of mCRPC patients do benefit from the molecule and that the antitumour response may be very durable in some patients. [J Clin Oncol 2018;36:5007] CAR T-cells have currently finished phase I trials with phase II trials being planned in the near future but it is still too early to draw concrete conclusions. [Prostate. 2016;76(14):1257–1270]

Lukman said future trials would also need to focus on the introduction of immunotherapy at an earlier stage, where the immunosuppressive mechanisms associated with advanced disease have not set in.

*KEYNOTE-028: Phase IB Study of pembrolizumab (MK-3475) in subjects with select advanced solid tumors
**KEYNOTE-199: Pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).