On March 15, 2022, Merck announced that it would discontinue the KEYLYNK-010 study. Results of interim analysis showed that KEYTRUDA (pembrolizumab) in combination with LYNPARZA (olaparib) failed to show an OS benifit in patients with metastatic castration-resistant prostate cancer (mCRPC) compared with controls (abiraterone or enzalutamide). This is another failure of immune checkpoint inhibitors (ICIs) in prostate cancer.

Why say "again"? So far, with the exception of pembrolizumab, ipilimumab, nivolumab, atezolizumab, and avelumab have failed to improve OS benefit.

There is only one small exception, as shown in the 2021 CSCO guidelines, pembrolizumab may be considered for patients with mCRPC after failure of prior novel endocrine therapy and docetaxel chemotherapy (category 3, Level III recommended).

This recommendation is based on the treatment of 149 cancer patients involving treatment regimens from 5 clinical trials, including patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors, of whom 2 with mCRPC, 1 with partial response and 1 with stable disease for more than 9 months.

On May 23, 2017, the U.S. Food and Drug Administration approved pembrolizumab for the treatment of unresectable or metastatic MSI-H or dMMR solid tumors with disease progression after prior therapy and no satisfactory alternative treatment options, that is, cancer-free species of indications. However, in prostate cancer, the proportion of this part of the population is only 2% to 3%.

Immunotherapy For Prostate Cancer: Good Starting and Disappointed Ending

Prostate cancer is one of the most common malignant tumors. Androgen deprivation therapy (ADT) is commonly used in the treatment of prostate cancer and can achieve a durable response. However, the majority of patients eventually develop resistance to ADT and are classified as castration-resistant prostate cancer (CRPC). According to the clinical situation, it can be further divided into non-metastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC). mCRPC is the focus of clinical research.

In recent years, immunotherapy has revolutionized the therapeutic landscape of cancer.  In prostate cancer, immunotherapy seems to have made a good start.  In 2010, sipuleucel-T was approved by the FDA for the treatment of mCRPC. Sipuleucel-t is a dendritic cell (DC) therapeutic tumor vaccine and the first therapeutic tumor vaccine to be approved. Sipuleucel-t, a DC vaccine, isolates a patient's DC from the blood, activates it outside the body, and then transfuses it back into the patient.

However, patients in the sipuleucel-T group were only able to extend survival by about four months compared with the control group.  The success of SIpuleucel-T makes ICI full of expectations.  Unfortunately, as mentioned at the beginning of the article, the results of a series of subsequent clinical trials were disappointing (below: partial collation of ICIs clinical trials for prostate cancer).  

Six Challenges of Immunotherapy For Prostate Cancer

1. Neoantigen and mutational burden

Neoantigens expressed on tumor cells can induce adequate activation of adaptive immunity. Tumor mutational burden correlates with ICI response. Data show that tumor types with high mutation burden (eg: melanoma, NSCLC, etc.) have an ICI response rate of at least 15%. However, both neoantigen levels and tumor mutational burden are lower in primary prostate cancer, which may be factors for poor ICI efficacy.

The data describe the number of mutations in each tumor cell type, with estimates of the number of neoantigens in different tumor types on the right.
Image from: Science. 2015; 348(6230): 69-74.

2. PD-1/PD-L1 expression level

At present, it is believed that the expression level of PD-1/PD-L1 cannot be equivalent to the level of ICI response, but it is an important evaluation index. Previous studies on the correlation between PD-1/PD-L1 expression levels in prostate cancer and the efficacy of ICIs have been inconsistent. Studies have shown that CRPC treated with enzalutamide has high expression of PD-L1, suggesting that ADT may activate adaptive immunity. Another study showed that ADT combined with abiraterone, prednisone, and leuprolide did not increase the expression level of PD-L1, and the response to ICI was not satisfactory. Therefore, more research is needed to improve the relationship between ADT and PD-1/PD-L1 expression levels.

3. Chronic Inflammation In The Immune Microenvironment

Prostate cancer has chronic inflammation caused by DNA damage, which may also result from DNA damage that causes cancer. Chronic inflammation can not only interfere with antitumor immune responses, but also promote tumor development. Cytokines produced in the inflammatory tumor microenvironment (TME) can promote tumor cell proliferation and migration, and induce tumor cell invasion, metastasis, and resistance to chemotherapeutics through epithelial-mesenchymal transition (EMT). Inflammatory cytokines also aggregate myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), both of which account for a major proportion of the TME. Data have shown that the severity of chronic inflammation is associated with five-year recurrence-free survival and recurrence prognosis.

Schematic diagram of the immune microenvironment of prostate cancer.
Image source: Investig Clin Urol. 2022; 63(1): 3-13.

4. Tumor-Associated Macrophages (TAMs) and Myeloid-Derived Suppressor Cells (MDSCs)

TAMs are abundant in the prostate cancer microenvironment and play an important role in inducing tumor cell proliferation, angiogenesis, immune regulation, and metastasis. In prostate cancer, the expression level of MDSC is about 40 times that of normal prostate. MDSC inhibits the antitumor effect of ICIs by disrupting the activation of antigen-presenting cells and cytotoxic T cells, suppressing the immune response to tumor cells. TAM, MDSC and tumor cells interact together to form the immunosuppressive microenvironment of prostate cancer, in which cytokines or signaling pathways such as CCL2/CCL5, GM-CSF, JAK/STAT and IL-4/6 play a role. 

5. Tumor-Associated Fibroblasts (CAFs)

CAFs are stromal cells capable of regulating the TME. Prostate cancer contains a large number of CAFs, which are constantly activated and promote the development of chronic inflammation. By recruiting regulatory T cells (Treg) and inducing T cell exhaustion, CAFs can inhibit the immune killing effect of CD8+ T cells. In this process, TGFβ, VEGFA, CXCL12 and other factors play a role.

6. Infiltration of CD8+ T cells

Tumors can be divided into four categories based on their immune status and response to immunotherapy: hot tumors, altered-excluded tumors, altered-immunosuppressed tumors, and cold tumors (below). T-cell infiltration was relatively abundant in hot and immune-rejecting tumors, but in the latter T cells were sequestered in peripheral areas. Altered-immunosuppressed tumor refer to T cells deficient, and whether they are classified as cold tumors depends on the degree of immunosuppressive changes.

Four classifications of tumors.
Image from: Nat Rev Drug Discov. 2019; 18(3): 197-218.

It is important to note that chronic inflammation is present in prostate cancer, but this does not mean that prostate cancer is a "hot" tumor. The chronic inflammation zone of prostate cancer is mainly in the benign area near the tumor, and only a few immune cells can be observed in the tumor area, so prostate cancer appears as a "cold" tumor.

Results from existing clinical trials of prostate cancer immunotherapy have been suboptimal. The continuous progress of basic research has gradually clarified the factors that affect the efficacy of ICIs. Antigen retrieval, initiation of antigen presentation, homing of immune cells, reactivation of T cells, recognition of tumor cells, and exertion of cell killing power are all future directions. Achieving optimal effects of immunotherapy requires precise modulation of antitumor immune responses, not only in prostate cancer cells, but also in the complex TME.

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References:

[1] Merck Announces KEYLYNK-010 Trial Evaluating KEYTRUDA (pembrolizumab) in Combination with LYNPARZA (olaparib) in Patients with Metastatic Castration-Resistant Prostate Cancer to Stop for Futility
[2] Immunotherapy for prostate cancer: Requirements for a successful regime transfer