ESMO 2018: Improving Treatment Outcome by Manipulating the Immune System

Munich, Germany (UroToday.com) Dr. Winald R. Gerritsen gave an overview of the role of immunotherapy in prostate cancer.

There have been several vaccinations that have been specifically developed for prostate cancer. These include:

  • Sipuleucel T – demonstrating a median four months overall survival advantage vs. placebo, with an immune response in 70% of patients
  • G-VAX – Two phase 3 studies comparing it vs. docetaxel had failed

 

  • Prostvac – A single phase 3 study had failed (compared to placebo). However, 50% had shown an immune response
  • DCVAC/PCa – A phase 3 study (VIABLE) had finished accrual, but results are not available yet
  • Curevac (an RNA based vaccine) – A single phase 2b study had failed

Immunotherapy with immune checkpoint inhibitors is a registered treatment for renal cell carcinoma and urothelial cancer. However, for prostate cancer, two phase 3 clinical trials with Ipilimumab had failed. A phase 2 study assessing the impact of pembrolizumab in mCRPC patients who have progressed on enzalutamide, demonstrated that three of the first ten patients experienced rapid PSA reductions to ≤ 0.2 ng/ml.1 Two of these three patients had measurable disease upon study entry; both achieved a partial response. A total of three patients experienced significant immune-related adverse events.

There have been other trials, including several ongoing combination trials with immune checkpoint inhibitors in prostate cancer. These include combinations of immune checkpoint inhibitors with chemotherapy, PARP inhibitors, Radium 223, Sipuleucel T, and others. There is some evidence to suggest that prostate cancer patients with microsatellite instability, which is a marker for mismatch repair gene mutations, might have a better response to immune checkpoint inhibitors. In a study bey Mehara N et al., presented in ESMO 2018, an in-depth assessment of metastatic prostate cancer subtypes by whole genome sequencing and multiplex immunohistochemistry was performed.2 This study demonstrated that approximately 15-25% of advanced prostate cancer patients have an immunogenic signature. Furthermore, a total of 7.7% of patients had a high tumor mutational burden (>10 mutations/Mb), 6.7% of patients had CDK12 bi-allelic inactivation and tandem duplication signature, and lastly, 12% of patients had BRCA mutations. 


It is known that DNA damage repair mutations are demonstrated in approximately a third of patients with prostate cancer.3 PARP inhibitors were found to be effective in this subset of patients, and there are currently several large, randomized trials which are underway, aiming to assess the role of PARP inhibitors in this specific setting. (4) An ongoing study combining the PARP inhibitor olaparib combined with the PD-L1 inhibitor durvalumab, has demonstrated interesting data in the first 17 patients. Of this initial cohort, ten patients (59%) had responses, composed of more than 50% PSA declines or partial responses according to conventional radiographic imaging.5 Responses were seen in all six patients who demonstrated having DNA damage repair mutations. The median progression-free survival was greater than 12 months in this population of patients, whose diseases were refractory to abiraterone and enzalutamide, and who for the most part, were already treated with chemotherapy. Unfortunately, there were some adverse effects, and these included colitis, synovitis, hearing changes, and optic neuritis.


The question how do PD-L1 inhibitors work together with PARP inhibitors, is still for the most part, unclear. According to one possible hypothesis, increased DNA damage leads to increased neoantigens presented by the cancer cell. Data have shown that neoantigen load may correlate with efficacy in patients treated with PD-1– or PD-L1–inhibiting agents.6 Another possible mechanism might be immunogenic modulation as a possible mechanism of synergy.7

Single-agent efficacy with PD-1 and PD-L1 inhibition in prostate cancer has been shown to be quite low. Therefore, several trials using multiple combinations of strategies may be defining a new role for these agents. These studies might help us understand the potential immunologic synergy. The results of these trials have the potential to make immune checkpoint inhibition therapeutically relevant in prostate cancer and could expand the pool of prospective responders in other cancers, where monotherapy with anti–PD-1/anti–PD-L1 lacks definitive universal benefit.

In summary, vaccinations induce immune responses in CRPC patients, and immune checkpoint inhibitors induce an immune response. There are several phase 3 trials with combinations of immune checkpoint inhibitors, which are enrolling/starting to enroll. Lastly, 25% of CRPC patients have mutations that induce an immunogenic response, and these might be the optimal candidates for immunotherapy.


 
Presented by: Winald R. Gerritsen, Professor, Chair, Department of Medical Oncology, Radboud University Medical Centre, Nijmegen, the Netherlands

References:
1. Graff JN et al. Oncotarget 2016
2. Mehara N et al. ESMO 2018
3. Robinson D, et al. Cell. 2015;161:1215-18.
4. Mateo J, et al. N Engl J Med. 2015;373:1697-708
5. Karzai F, et al. J Clin Oncol. 2017
6. McGranahan N, et al. Science. 2016;351:1463-9.
7. Hodge JW, et al. Int J Cancer. 2013;133:624-36

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 European Society for Medical Oncology Congress (#ESMO18), October 19-23,  2018, Munich Germany

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