CCTG IND 232: A phase II study of durvalumab with or without tremelimumab in patients with metastatic castration resistant prostate cancer (mCRPC)

Hotte, S. J.; Winquist, Eric; N., Kim; Ellard, Susan; Sridhar, Srikala S.; Emmenegger, Urban; Salim, Muhammad; Iqbal, Nayyer; Canil, Christina; Kollmannsberger, C.; Hansen, Aaron R.; Lalani, Aly-Khan A.; Gingerich, Joel Roger; Finch, Daygen L.; Cabanero, Michael; Wyatt, Alexander W.; Tu, Daniel C.; Seymour, Lesley; Smoragiewicz, Martin

doi:10.1093/annonc/mdz394.044

Cited by 14 publications

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“…Initial search in electronic databases revealed 831 results which underwent initial assessment. Twenty three publications underwent full-text assessment, and finally, eight publications (six journal papers [19][20][21][22][23][24], and two meeting abstracts [25,26]) were considered. A total number of 2768 patients with mCRPC were included in the pooled analyses, after exclusion of one cohort (n = 59 patients) from one study not eligible for subgroup analysis [21].…”

Section: Search Resultsmentioning

confidence: 99%

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

Fahmy

Alhakamy

Khairul-Asri

et al. 2021

JPM

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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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Section: Search Resultsmentioning

confidence: 99%

“…Risk of bias assessment is available in Table 2 for the five non-randomized trials [19][20][21][22]26], and in Figure 2 for the three randomized trials [23][24][25].…”

Section: Search Resultsmentioning

confidence: 99%

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

Fahmy

Alhakamy

Khairul-Asri

et al. 2021

JPM

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“…The first trial examined durvalumab with or without tremelimumab following enzalutamide or abiraterone and no more than one taxane chemotherapy (NCT02788773), and has reported preliminary results, which have not been published. 38 The second trial was a phase II study of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg (IPI1+NIVO3) with or without enzalutamide (n=15 in each cohort) in AR-V7 + mCRPC irrespective of prior chemotherapy (NCT02601014). 15 17 Among patients with measurable disease, this trial reported objective responses in two patients, leading the authors to conclude that the combination was ineffective in the overall AR-V7 + study population, though higher response rates were observed among DDR + patients.…”

Section: Discussionmentioning

confidence: 99%

Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

Subudhi

Siddiqui

Aparicio

et al. 2021

J Immunother Cancer

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BackgroundImmune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone.HypothesisCombined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone.Patients and methodsIn this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline.ResultsTwenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints.ConclusionsTremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment.Trial registration numberNCT03204812.

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“…The most common TRAEs were grade 2 or less and the most common grade 3/4 TRAEs were diarrhea and elevated transaminitis. There was no grade 5 TRAEs [ 26 ]…”

Section: Ctla-4 and Pd-1/pd-l1 Combination Therapymentioning

confidence: 99%

Immune Checkpoint Inhibitors in Prostate Cancer

Venkatachalam

McFarland

Agarwal

et al. 2021

Cancers

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Metastatic prostate cancer is a lethal disease with limited treatment options. Immune checkpoint inhibitors have dramatically changed the treatment landscape of multiple cancer types but have met with limited success in prostate cancer. In this review, we discuss the preclinical studies providing the rationale for the use of immunotherapy in prostate cancer and underlying biological barriers inhibiting their activity. We discuss the predictors of response to immunotherapy in prostate cancer. We summarize studies evaluating immune checkpoint inhibitors either as a single agent or in combination with other checkpoint inhibitors or with other agents such as inhibitors of androgen axis, poly ADP-ribose polymerase (PARP), radium-223, radiotherapy, cryotherapy, tumor vaccines, chemotherapy, tyrosine kinase inhibitors, and granulocyte-macrophage colony-stimulating factor. We thereafter review future directions including the combination of immune checkpoint blockade with inhibitors of adenosine axis, bispecific T cell engagers, PSMA directed therapies, adoptive T-cell therapy, and multiple other miscellaneous agents.

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CCTG IND 232: A phase II study of durvalumab with or without tremelimumab in patients with metastatic castration resistant prostate cancer (mCRPC)

Cited by 14 publications

References 0 publications

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

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

Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment

Immune Checkpoint Inhibitors in Prostate Cancer

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