cabozantinib and abiraterone

Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

Topics: Androstenes; Anilides; Antineoplastic Agents; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Carcinoma; Dasatinib; Denosumab; Diphosphonates; Docetaxel; Humans; Imidazoles; Male; Mitoxantrone; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Radioisotopes; Radium; Taxoids; Zoledronic Acid

This review will describe the management of patients with prostate cancer and bone metastases with a particular emphasis on recent advances in this area.. Two osteoclast-targeted agents have been shown to decrease the incidence of skeletal-related events in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. These agents are the bisphosphonate zoledronic acid and the monoclonal antibody denosumab. Recent advances in the field include the approval of several agents shown to extend survival in mCRPC. Among these agents, the androgen-pathway inhibitors, abiraterone and enzalutamide, are shown to decrease the incidence of skeletal-related events, whereas the radiopharmaceutical radium-223 is shown to reduce the incidence of symptomatic skeletal event. Cabozantinib, an agent in development, has shown encouraging activity in patients with mCRPC and bone metastases; definitive phase III trials of this agent are underway. Phase III metastasis-prevention trials are also underway in nonmetastatic CRPC.. Osteoclast-targeted agents reduce skeletal-related events in mCRPC. Disease-modifying agents also reduce the skeletal morbidity associated with mCRPC. Multiple agents are now available to reduce the skeletal morbidity of prostate cancer, whereas agents in development may provide additional options in the future.

Topics: Androstenes; Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Bone Density Conservation Agents; Bone Neoplasms; Denosumab; Diphosphonates; Fractures, Spontaneous; Humans; Imidazoles; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyridines; Radioisotopes; Radium; Zoledronic Acid

Recent advances in tumor biology have made remarkable achievements in the development of therapy for metastatic castrate-resistant prostate cancer. These advances reflect a growing appreciation for the role of the tumor microenvironment in promoting prostate cancer progression. Prostate cancer is no longer viewed predominantly as a disease of abnormally proliferating epithelial cells but rather as a disease of complex interactions between prostate cancer epithelial cells (epithelial compartment) and the surrounding tissues (stromal compartment) in which they reside. For example, prostate cancers frequently metastasize to bone, an organ that contains a microenvironment rich in extracellular matrix proteins and stromal cells including hematopoietic cells, osteoblasts, osteoclasts fibroblasts, endothelial cells, adipocytes, immune cells, and mesenchymal stem cells. Multiple signaling pathways provide crosstalk between the epithelial and the stromal compartments to enhance tumor growth, including androgen receptor signaling, tyrosine kinase receptor signaling, and immune surveillance. The rationale to disrupt this "two-compartment" crosstalk has led to the development of drugs that target tumor stromal elements in addition to the cancer epithelial cell.

Topics: Androstenes; Androstenols; Angiogenesis Inhibitors; Anilides; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Atrasentan; Benzamides; Bevacizumab; Biomarkers, Tumor; Bone Remodeling; Cancer Vaccines; Clinical Trials as Topic; Clusterin; Dasatinib; Denosumab; Endothelin-1; Humans; Immunotherapy; Indoles; Ipilimumab; Male; Mice; Mice, SCID; Molecular Targeted Therapy; Nitriles; Orchiectomy; Phenylthiohydantoin; Prostate-Specific Antigen; Prostatic Neoplasms; Pyridines; Pyrimidines; Pyrroles; Pyrrolidines; RANK Ligand; Receptor Cross-Talk; Receptors, Androgen; Signal Transduction; Sunitinib; Taxoids; Thiazoles; Tissue Extracts; Treatment Failure; Tumor Microenvironment; Xenograft Model Antitumor Assays

Cabozantinib inhibits multiple receptor tyrosine kinases, including the TAM kinase family, and may enhance response to immune checkpoint inhibitors. One cohort of the ongoing phase Ib COSMIC-021 study (NCT03170960) evaluating cabozantinib plus the PD-L1 inhibitor atezolizumab in men with metastatic castration-resistant prostate cancer (mCRPC) that has progressed in soft tissue on/after enzalutamide and/or abiraterone treatment for metastatic disease has shown promising efficacy. Here, we describe the rationale and design of a phase III trial of cabozantinib plus atezolizumab versus a second novel hormone therapy (NHT) in patients who have previously received an NHT for mCRPC, metastatic castration-sensitive PC or nonmetastatic CRPC and have measurable visceral disease and/or extrapelvic adenopathy - a population with a significant unmet need for treatment options.

Topics: Adenocarcinoma; Androstenes; Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Benzamides; Humans; Immune Checkpoint Inhibitors; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Receptor Protein-Tyrosine Kinases

Abiraterone improves the overall survival of men with metastatic castration-resistant prostate cancer. However, de novo or adaptive resistance to abiraterone limits its activity. Rational combinations of drugs with different mechanisms of action that overcome resistance mechanisms may improve the efficacy of therapy. To that end, we studied the molecular and phenotypic effects of the combination of cabozantinib plus abiraterone.. Three prostate cancer cell lines were used to interrogate the in vitro molecular and antiproliferative effects of the single agents and combination of cabozantinib and abiraterone. The in vivo impact of the combination was assessed using the LAPC4-CR xenograft mouse model.. In vitro proliferation studies demonstrated single-agent doses between 2 μmol/L and 10 μmol/L for abiraterone and cabozantinib inhibit prostate cancer cell proliferation in a dose-dependent manner, and the anticancer activity of abiraterone is enhanced when combined with cabozantinib. In vivo LAPC4-CR xenograft mouse studies also showed that cabozantinib can improve the antitumor activity of abiraterone. Cabozantinib, a multiple receptor tyrosine kinase inhibitor, enhances the ability of abiraterone to inhibit AR activity in a cell line-dependent manner. In addition, our cell line studies demonstrate abiraterone-stimulated insulin-like growth factor I receptor (IGFIR) phosphorylation with downstream activation of MEK1/2 and ERK1/2, and that this potential adaptive resistance mechanism was inhibited by cabozantinib.. Cabozantinib can enhance the efficacy of abiraterone by blocking multiple compensatory survival mechanisms, including IGFIR activation, and supports the assessment of the combination in a clinical trial.

Topics: Androstenes; Anilides; Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Antagonism; Drug Resistance, Neoplasm; Humans; Male; Mice; Phosphorylation; Prostatic Neoplasms; Pyridines; Receptor Protein-Tyrosine Kinases; Receptor, IGF Type 1; Receptors, Androgen; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Until 2010, chemotherapy with docetaxel was the only approved agent for treatment of metastatic castrate resistant prostate cancer (mCRPC). Since then, the therapeutic landscape of mCRPC has changed rapidly. Multiple novel agents have received regulatory approval after demonstrating improved overall survival in separate randomized Phase 3 studies. These include immunotherapeutic agent sipuleucel-T, androgen axis inhibitors abiraterone and enzalutamide, and a novel microtubule inhibitor cabazitaxel. More recently, radium-223, a bone-targeting alpha emitting radiopharmaceutical, was reported to improve skeletal related events, as well as overall survival in a Phase 3 randomized study. Additionally, there are several promising agents in the advanced stages of clinical development. Here, we describe the agents recently shown to improve overall survival, and those that have reached the advanced stages of development in Phase 3 clinical trials. We will also propose a strategy for optimal sequencing of these agents in the treatment of mCRPC.

Topics: Androstenes; Androstenols; Anilides; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Disease-Free Survival; Humans; Imidazoles; Ipilimumab; Male; Naphthalenes; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Quinolines; Quinolones; Radioisotopes; Radium; Taxoids; Thionucleotides; Tissue Extracts