scholarly journals Oncological Response and Predictive Biomarkers for the Checkpoint Inhibitors in Castration-Resistant Metastatic Prostate Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 12 (1) ◽  
pp. 8
Author(s):  
Omar Fahmy ◽  
Nabil A. Alhakamy ◽  
Mohd G. Khairul-Asri ◽  
Osama A. A. Ahmed ◽  
Usama A. Fahmy ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Metastatic Prostate Cancer ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Castration Resistant Prostate Cancer ◽  
Overall Response ◽  
Castration Resistant

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.

The Current Role of Immunotherapy in mCRPC: A Systematic Review

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.

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

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.

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

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.

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

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.

Immune-checkpoint inhibitors and metastatic prostate cancer therapy: Learning by making mistakes

2020 ◽  
Vol 88 ◽  
pp. 102057 ◽  
Author(s):  
Mélanie Claps ◽  
Alessia Mennitto ◽  
Valentina Guadalupi ◽  
Pierangela Sepe ◽  
Marco Stellato ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Metastatic Prostate Cancer ◽  
Checkpoint Inhibitors ◽  
Prostate Cancer Therapy

scholarly journals Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, Other Than Abscopal Effect: A Systematic Review

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 539 ◽  
Author(s):  
Vito Longo ◽  
Oronzo Brunetti ◽  
Amalia Azzariti ◽  
Domenico Galetta ◽  
Patrizia Nardulli ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Research Field ◽  
Oncolytic Viruses ◽  
Abscopal Effect ◽  
Tumor Mutational Burden ◽  
The Impact

Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.

scholarly journals Strategies to Improve Cancer Immune Checkpoint Inhibitors Efficacy, other than Abscopal Effect: A Systematic Review

2019 ◽  
Author(s):  
Vito Longo ◽  
oronzo Brunetti ◽  
Amalia Azzariti ◽  
Domenico Galetta ◽  
Patrizia Nardulli ◽  
...  
Keyword(s):  
Systematic Review ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Research Field ◽  
Oncolytic Viruses ◽  
Abscopal Effect ◽  
Improve Response Rate ◽  
The Impact

Despite the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitor-urinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a high sensibility to immune checkpoint inhibitors, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitors receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.

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