A Systematic Review of the Emerging Role of Immune Checkpoint Inhibitors in Metastatic Castration-resistant Prostate Cancer: Will Combination Strategies Improve Efficacy?

Recently, checkpoint inhibitors have been investigated in metastatic prostate cancer, however their overall effect is unclear and needs to be further investigated. Objectives: The aim of this systematic review is to investigate the oncological response of metastatic castration-resistant prostate cancer patients to immune checkpoint inhibitors. Methods: Based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement, a systematic review of the literature was conducted through online electronic databases and the American Society of Clinical Oncology (ASCO) Meeting Library. Eligible publications were selected after a staged screening and selection process. RevMan 5.4 software was employed to run the quantitative analysis and forest plots. Risk of bias assessment was conducted using the Cochrane tool and Newcastle–Ottawa Scale for the randomized and non-randomized trials, respectively. Results: From the 831 results retrieved, 8 studies including 2768 patients were included. There was no significant effect on overall survival (OS) (overall response (OR) = 0.98; Z = 0.42; p = 0.67). Meanwhile, progression-free survival (PFS) was significantly better with immune checkpoint inhibitors administration (OR = 0.85; Z = 3.9; p < 0.0001). The subgroup analysis for oncological outcomes based on programmed death ligand 1 (PD-L1) positivity status displayed no significant effect, except on prostate-specific antigen response rate (PSA RR) (OR = 3.25; Z = 2.29; p = 0.02). Based on DNA damage repair (DDR), positive patients had a significantly better PFS and a trend towards better OS and overall response rate (ORR); the ORR was 40% in positive patients compared to 20% in the negative patients (OR = 2.46; Z = 1.3; p = 0.19), while PSA RR was 23.5% compared to 14.3% (OR = 1.88; Z = 0.88; p = 0.38). Better PFS was clearly associated with DDR positivity (OR = 0.70; Z = 2.48; p = 0.01) with a trend towards better OS in DDR positive patients (OR = 0.71; Z = 1.38; p = 0.17). Based on tumor mutation burden (TMB), ORR was 46.7% with high TMB versus 8.8% in patients with low TMB (OR = 11.88; Z = 3.0; p = 0.003). Conclusions: Checkpoint inhibitors provide modest oncological advantages in metastatic castration-resistant prostate cancer. There are currently no good predictive indicators that indicate a greater response in some patients.

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Biomarkers of response to immune checkpoint inhibitors for metastatic castration resistant prostate cancer: looking for the needle in the haystack

Annals of Translational Medicine ◽

10.21037/atm.2020.03.78 ◽

2020 ◽

Vol 8 (14) ◽

pp. 894-894

Author(s):

Husam A. Alqaisi ◽

Esmail Al-ezzi ◽

Aaron R. Hansen

Keyword(s):

Prostate Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

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Immune Checkpoint Inhibitors: A Promising Treatment Option for Metastatic Castration-Resistant Prostate Cancer?

International Journal of Molecular Sciences ◽

10.3390/ijms22094712 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4712

Author(s):

Vicenç Ruiz de Porras ◽

Juan Carlos Pardo ◽

Lucia Notario ◽

Olatz Etxaniz ◽

Albert Font

Keyword(s):

Prostate Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Predictive Biomarkers ◽

Current Status ◽

Castration Resistant Prostate Cancer ◽

Mechanisms Of Resistance ◽

Castration Resistant

Since 2010, several treatment options have been available for men with metastatic castration-resistant prostate cancer (mCRPC), including immunotherapeutic agents, although the clinical benefit of these agents remains inconclusive in unselected mCRPC patients. In recent years, however, immunotherapy has re-emerged as a promising therapeutic option to stimulate antitumor immunity, particularly with the use of immune checkpoint inhibitors (ICIs), such as PD-1/PD-L1 and CTLA-4 inhibitors. There is increasing evidence that ICIs may be especially beneficial in specific subgroups of patients with high PD-L1 tumor expression, high tumor mutational burden, or tumors with high microsatellite instability/mismatch repair deficiency. If we are to improve the efficacy of ICIs, it is crucial to have a better understanding of the mechanisms of resistance to ICIs and to identify predictive biomarkers to determine which patients are most likely to benefit. This review focuses on the current status of ICIs for the treatment of mCRPC (either as monotherapy or in combination with other drugs), mechanisms of resistance, potential predictive biomarkers, and future challenges in the management of mCRPC.

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Immune Checkpoint Blockade for Prostate Cancer: Niche Role or Next Breakthrough?

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_278853 ◽

2020 ◽

pp. e89-e106

Author(s):

Daniel Vargas P. de Almeida ◽

Lawrence Fong ◽

Matthew B. Rettig ◽

Karen A. Autio

Keyword(s):

Prostate Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Single Agent ◽

Small Subset ◽

Castration Resistant Prostate Cancer ◽

Primary Resistance ◽

Cancer Management ◽

Castration Resistant

A number of trials have evaluated the use of single-agent immune checkpoint inhibitors for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The benefit appears to be limited to a small subset of patients, such as those with tumors with microsatellite instability, highlighting the importance of biomarkers to identify which patients may be more likely to respond. Given the lack of efficacy for most patients with mCRPC, our understanding of the mechanisms of primary resistance to checkpoint inhibitors and of the tumor immune microenvironment in prostate cancer is critical. Knowledge gained in these key areas will allow for the identification of novel combination therapies that will circumvent resistance mechanisms and should be tested in clinical trials. Improving our understanding of the effects of androgen deprivation therapy on immune cells and of the most favorable disease setting (e.g., biochemically recurrent vs. castration-resistant prostate cancer) may aid in the optimal use of checkpoint inhibitors in combination with other agents. If successful, this may move immune checkpoint inhibitors into the treatment armamentarium of prostate cancer management.

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Putting the Pieces Together: Completing the Mechanism of Action Jigsaw for Sipuleucel-T

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa021 ◽

2020 ◽

Vol 112 (6) ◽

pp. 562-573

Author(s):

Ravi A Madan ◽

Emmanuel S Antonarakis ◽

Charles G Drake ◽

Lawrence Fong ◽

Evan Y Yu ◽

...

Keyword(s):

Prostate Cancer ◽

Immune Response ◽

T Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Phase Iii ◽

Immune Memory ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant

Abstract Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.

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The Current Role of Immunotherapy in mCRPC: A Systematic Review

Austin Journal of Clinical Case Reports ◽

10.26420/austinjclincaserep.2021.1222 ◽

2021 ◽

Vol 8 (7) ◽

Author(s):

Dalibey H ◽

◽

Hansen TF ◽

Zedan AH ◽

◽

...

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

Overall Survival ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Specific Antigen ◽

Treatment Modalities ◽

Significant Difference

Background: The development of immunotherapy has shown promising results in several malignant diseases, including prostate cancer, calling for a systematic review of the current literature. This review aims to evaluate the present data and prospects of immune checkpoint inhibitors in metastatic Castration Resistant Prostate Cancer (mCRPC). Methods: Articles were identified via a systematic search of the electronic database Pubmed, in accordance with the PICO process and following the PRISMA guidelines. Articles in English studying immune checkpoint inhibitors in patients with mCRPC published between March 2010 and March 2020 were eligible for inclusion. Endpoints of interest were Overall Survival (OS), Progression-Free Survival (PFS), clinical Overall Response Rate (ORR), and Prostate-Specific Antigen (PSA) response rate. Results: Ten articles were identified as eligible for inclusion. The studies primarily explored the use of Ipilimumab, a CTLA-4 inhibitor, and Pembrolizumab, a PD-1 inhibitor. These drugs were both used either as monotherapy or in combination with other treatment modalities. The largest trial included in the review demonstrated no significant difference in overall survival between the intervention and placebo. However, two studies presented promising data combing immunotherapy and immune vaccines. Grade 3 and 4 adverse events ranging from 10.1% to 82.3%, whit diarrhea, rash, and fatigue were the most frequently reported. Forty relevant ongoing trials were identified exploring immunotherapy with or without a parallel treatment modality. Conclusion: Overall, the current data shows that the effect of immune checkpoint inhibitors as monotherapy may have limited impact on mCRPC, and the results from ongoing combinational trials are eagerly awaited.

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The role of immune checkpoint inhibitors in prostate cancer

Annals of Agricultural and Environmental Medicine ◽

10.26444/aaem/96331 ◽

2019 ◽

Vol 26 (1) ◽

pp. 120-124

Author(s):

Gabriel Surdacki ◽

Aneta Szudy-Szczyrek ◽

Aneta Gorący ◽

Katarzyna Chyl-Surdacka ◽

Marek Hus

Keyword(s):

Prostate Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors

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VEGF and Immune Checkpoint Inhibition for Prevention of Brain Metastases: Systematic Review and Meta-analysis

Neurology ◽

10.1212/wnl.0000000000012642 ◽

2021 ◽

pp. 10.1212/WNL.0000000000012642

Author(s):

Alireza Mansouri ◽

Varun Padmanaban ◽

Dawit Aregawi ◽

Michael Glantz

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Small Cell ◽

Small Cell Lung ◽

Vegf Inhibitors

Objective:We conducted a systematic review and meta-analysis to investigate the role of VEGF inhibitors and immune checkpoint inhibitors (ICIs) in preventing the development of brain metastasis (BMs).Methods:We searched MEDLINE, EMBASE, Cochrane Database, Google Scholar between January 1, 2000 and June 1, 2020. Included studies were randomized controlled trials (RCTs) of adults with systemic cancer which reported incidence of BMs treated with and without VEGF inhibitors, and observational studies of adults with systemic cancer which reported incidence of BMs treated with and without ICIs (there were no RCTs addressing the ICI question). Pooled relative risks (RR) were computed utilizing a binary random-effects model.Results:A search for VEGF and incidence of new BMs revealed 7 studies (6212 patients with breast, colon and non-small cell lung cancer). Meta-analysis showed a lower incidence of new BMs compared to control (RR 0.71, 95% CI: 0.56-0.89, p=0.003). A search for ICIs and incidence of new BMs yielded 8 studies (732 patients with non-small cell lung cancer or metastatic melanoma) where ICIs were used as an adjunct to radiosurgery. Meta-analysis showed a lower incidence of out-of-treatment-field BMs with ICI inhibitors compared to controls at 1 year (RR 0.65, 95% CI: 0.49-0.88, p=0.005). The overall GRADE score for the evidence evaluating the role of bevacizumab and immune checkpoint inhibitors was high and moderate, respectively.Conclusion:VEGF and immune checkpoint inhibitors may have a role in prophylaxis against brain metastases in patients with solid tumors.

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