Pembrolizumab (pembro) plus enzalutamide (enza) in patients (pts) with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort C efficacy, safety, and biomarker results.

Conter, Henry Jacob; Shore, Neal D.; Berry, William R.; Fong, Peter; Rodriguez, Jose M. Mateos; Appleman, Leonard Joseph; Todenhöfer, Tilman; Gravis, G.; Laguerre, Brigitte; Retz, Margitta; Romano, Emanuela; Mourey, Loïc; Bono, Johann S. de; Kam, Audrey E.; Emmenegger, Urban; Wu, Haiyan; Qiu, Ping; Schloss, Charles; Yu, Evan Y.

doi:10.1200/jco.2020.38.15_suppl.5545

Cited by 5 publications

(8 citation statements)

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“…In cohort 5, the DCR was 51% [62]. Cohort C of the phase Ib/II clinical trial KEYNOTE 365 is evaluating the combination of pembrolizumab with enzalutamide in patients with mCRPC who were intolerant to or had progression on abiraterone [63]. The primary endpoints were PSA response rate, ORR, and safety.…”

Section: Pembrolizumab + Enzalutamidementioning

confidence: 99%

“…In patients with measurable disease and ≥ 27 weeks of follow-up, the ORR was 12%, and the DCR was 32%. Median DOR has not yet been reached, radiological PFS was 6.1 months, and median OS was 20.4 months [ 63 ]. A T-cell-inflamed gene expression profile was not significantly associated with ORR or PSA response [ 63 ].…”

Section: Immune Checkpoint Inhibitors: Combination Therapiesmentioning

confidence: 99%

“…Median DOR has not yet been reached, radiological PFS was 6.1 months, and median OS was 20.4 months [ 63 ]. A T-cell-inflamed gene expression profile was not significantly associated with ORR or PSA response [ 63 ]. The combination is being evaluated in the phase III KEYNOTE-641 (NCT03834493) study in patients with mCRPC [ 63 ].…”

Section: Immune Checkpoint Inhibitors: Combination Therapiesmentioning

confidence: 99%

“…A T-cell-inflamed gene expression profile was not significantly associated with ORR or PSA response [ 63 ]. The combination is being evaluated in the phase III KEYNOTE-641 (NCT03834493) study in patients with mCRPC [ 63 ].…”

Section: Immune Checkpoint Inhibitors: Combination Therapiesmentioning

confidence: 99%

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Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Rathi

McFarland

Nussenzveig

et al. 2020

Drugs

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Immunotherapies have shown remarkable success in the treatment of multiple cancer types; however, despite encouraging preclinical activity, registration trials of immunotherapy in prostate cancer have largely been unsuccessful. Sipuleucel-T remains the only approved immunotherapy for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer based on modest improvement in overall survival. This immune evasion in the case of prostate cancer has been attributed to tumor-intrinsic factors, an immunosuppressive tumor microenvironment, and host factors, which ultimately make it an inert ‘cold’ tumor. Recently, multiple approaches have been investigated to turn prostate cancer into a ‘hot’ tumor. Antibodies directed against programmed cell death protein 1 have a tumor agnostic approval for a small minority of patients with microsatellite instability-high or mismatch repair-deficient metastatic prostate cancer. Herein, we present an overview of the current immunotherapy landscape in metastatic castration-resistant prostate cancer with a focus on immune checkpoint inhibitors. We describe the results of clinical trials of immune checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer; either as single agents or in combination with other checkpoint inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors, tyrosine kinase inhibitors, novel hormonal therapies, chemotherapies, and radioligands. Finally, we review upcoming immunotherapies, including novel monoclonal antibodies, chimeric-antigen receptor (CAR) T cells, Bi-Specific T cell Engagers (BiTEs), therapies targeting the adenosine pathway, and other miscellaneous agents.

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Section: Pembrolizumab + Enzalutamidementioning

confidence: 99%

Section: Immune Checkpoint Inhibitors: Combination Therapiesmentioning

confidence: 99%

Section: Immune Checkpoint Inhibitors: Combination Therapiesmentioning

confidence: 99%

Section: Immune Checkpoint Inhibitors: Combination Therapiesmentioning

confidence: 99%

See 2 more Smart Citations

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Rathi

McFarland

Nussenzveig

et al. 2020

Drugs

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“…Metastatic castration-resistant prostate cancer (mCRPC) continues to be a major cause of complications and death among men [1][2][3]. Management of mCRPC is still controversial [3].…”

Section: Introductionmentioning

confidence: 99%

Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study

et al. 2021

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Background The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining. Methods Consecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs). Results In total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43–85] and PA: n = 106, 65 years [range, 45–82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2–42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3–27.6) in the PE group versus 18.3 months (95% CI, 16.5–20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39–0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7–7.8] for PE vs. 4.9 months for PA (95% CI, 3.2–6.4) for PA; HR 0.55, 95% CI, 0.41–0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable. Conclusions Among selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.

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Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer

Choudhury,

Kwak,

Cheung

et al. 2024

Cancer Immunology Research

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The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was −0.7 (range: −9.3 to 4.7) with R223+P and 0.1 (−11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was −0.6 (−7.4 to 5.3) with R223+P and −1.3 (−3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7–11.0) and 16.9 months [12.7–not reached (NR)], respectively, with R223+P and 5.7 (2.6–NR) and 16.0 (9.0–NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.

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Pembrolizumab (pembro) plus enzalutamide (enza) in patients (pts) with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 cohort C efficacy, safety, and biomarker results.

Cited by 5 publications

References 0 publications

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Evolving Role of Immunotherapy in Metastatic Castration Refractory Prostate Cancer

Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study

Randomized Phase II Study Evaluating the Addition of Pembrolizumab to Radium-223 in Metastatic Castration-resistant Prostate Cancer

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