Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial

Sharma, Padmanee; Pachynski, Russell K.; Narayan, Vivek; Fléchon, Aude; Gravis, Gwénaëlle; Galsky, Matthew D.; Mahammedi, Hakim; Patnaik, Akash; Subudhi, Sumit K.; Ciprotti, Marika; Şimşek, Burçin; Saci, Abdel; Hu, Yanhua; Han, G. Celine; Fizazi, Karim

doi:10.1016/j.ccell.2020.08.007

Cited by 232 publications

(212 citation statements)

References 55 publications

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“…According to the preliminary results of an ongoing trial, PCa patients with tumors having a PD-L1 level of at least 1%, HR deficiency mutations, DNA damage repair mutations, or a TMB greater than the median of 74.5 mutations showed enhanced responses to a combined nivolumab/ipilimumab treatment [ 65 ]. Our subject has signs of HR deficiency (the most dominant mutational signature), an ATM mutation of unknown clinical significance, a BRCA2 fusion transcript that likely reduces full BRCA2 functionality, and a significantly higher TMB than the median for PCa [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Nakken

Lilleby

Switlyk

et al. 2021

JPM

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Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion of PTEN and a fusion transcript involving BRCA2. The gene expression patterns in the tumor biopsy were also strikingly similar to prostate tumor samples from TCGA. Furthermore, we detected multiple lines of evidence for homologous recombination repair deficiency (HRD), including a dominant contribution by mutational signature SBS3, which is specifically attributed to HRD. On the basis of the genomic and transcriptomic findings, and in light of the clinical case presentation, we discussed the personalized treatment options that exist for this patient and the various challenges that one faces in the process of translating high-throughput sequencing data towards treatment regimens.

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Section: Discussionmentioning

confidence: 99%

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Nakken

Lilleby

Switlyk

et al. 2021

JPM

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show abstract

“…In another study with 2 cohorts of 90 pre-chemotherapy (n = 45) and post-chemotherapy ( n = 45) mCRPC patients treated with combined ipilimumab and nivolumab (CheckMate 650), ORR, PSA response, and median OS were 25% vs. 10%, 17.6% vs. 10% and 19.0 vs. 15.2-months, respectively. Four treatment-related deaths were observed and patients with higher TMB, homologous recombination deficiency (HRD)-positive status, DDR-positive status, and PD-L1 ≥ 1% had better response rates [ 32 ].…”

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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“…This impressive data was compromised by observed adverse reactions (diarrhea, hypothyroidism, fatigue, skin rash, etc.) and fatalities that intercepted the use of this approach [82]. More trials with modified treatment dosage and duration approaches are ongoing to minimise these adverse reactions associated with nivolumab and ipilimumab dual-combination treatment.…”

Section: Cytotoxic T-lymphocyte Antigenmentioning

confidence: 99%

Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

Kgatle

Boshomane

Lawal

et al. 2021

IJMS

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Emerging research demonstrates that co-inhibitory immune checkpoints (ICs) remain the most promising immunotherapy targets in various malignancies. Nonetheless, ICIs have offered insignificant clinical benefits in the treatment of advanced prostate cancer (PCa) especially when they are used as monotherapies. Current existing PCa treatment initially offers an improved clinical outcome and overall survival (OS), however, after a while the treatment becomes resistant leading to aggressive and uncontrolled disease associated with increased mortality and morbidity. Concurrent combination of the ICIs with radionuclides therapy that has rapidly emerged as safe and effective targeted approach for treating PCa patients may shift the paradigm of PCa treatment. Here, we provide an overview of the contextual contribution of old and new emerging inhibitory ICs in PCa, preclinical and clinical studies supporting the use of these ICs in treating PCa patients. Furthermore, we will also describe the potential of using a combinatory approach of ICIs and radionuclides therapy in treating PCa patients to enhance efficacy, durable cancer control and OS. The inhibitory ICs considered in this review are cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD1), V-domain immunoglobulin suppressor of T cell activation (VISTA), indoleamine 2,3-dioxygenase (IDO), T cell Immunoglobulin Domain and Mucin Domain 3 (TIM-3), lymphocyte-activation gene 3 (LAG-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), B7 homolog 3 (B7-H3) and B7-H4.

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Nivolumab Plus Ipilimumab for Metastatic Castration-Resistant Prostate Cancer: Preliminary Analysis of Patients in the CheckMate 650 Trial

Cited by 232 publications

References 55 publications

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology

Immune Checkpoint Inhibitors in Prostate Cancer

Immune Checkpoints, Inhibitors and Radionuclides in Prostate Cancer: Promising Combinatorial Therapy Approach

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