cabozantinib and Prostatic-Neoplasms--Castration-Resistant

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

Over 80% of men with castration-resistant prostate cancer have bone metastases. This condition can dramatically impact quality of life and is associated with short-term survival. Consequently, the development of bone-targeted therapies is a relevant topic on prostate cancer management. Hepatocyte growth factor receptor and vascular endothelial growth factor signaling pathways have been identified to play a role in prostate cancer progression and bone metastasis and are potential targets for therapeutic intervention. Early-phase studies have shown encouraging responses in bone metastases and pain control with cabozantinib, a multi-tyrosine kinase inhibitor targeting hepatocyte growth factor receptor and vascular endothelial growth factor receptor. Despite striking responses seen in some patients, preliminary results from a pivotal Phase III study have failed to produce survival benefit. This review encompasses preclinical and clinical data of cabozantinib in metastatic castration-resistant prostate cancer highlighting future research options for this agent.

Topics: Anilides; Animals; Antineoplastic Agents; Bone Neoplasms; Humans; Male; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines; Quality of Life; Receptor Protein-Tyrosine Kinases; Survival Rate

The landscape of castration-resistant prostate carcinoma has changed completely in the last few years, with the approval of four new agents with proven benefit in overall survival. Abiraterone, cabazitaxel, enzalutamide and radium-223 dichloride have been added to the armamentarium of available agents for the treatment of these patients. We still lack information about which agent works best in an individual patient and how to optimally use them in a sequential strategy. Cabozantinib, a targeted agent against MET and vascular endothelial growth factor receptor-2, has shown promising results and could become the first targeted therapy to be approved for castration-resistant prostate carcinoma. This paper reviews the clinical development of cabozantinib in prostate cancer and future research possibilities for this drug.

Topics: Anilides; Antineoplastic Agents; Clinical Trials as Topic; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases

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

The treatment landscape in metastatic castration-resistant prostate cancer (mCRPC) has significantly changed in the recent years. We provide an updated summary of the new therapeutic agents in this disease and discuss open questions and future challenges.. mCRPC is now known to frequently retain sensitivity to hormonal manipulation even after the development of castration resistance, and both the androgen synthesis inhibitor abiraterone and the androgen-receptor antagonist enzalutamide have recently shown to prolong survival in mCRPC patients after chemotherapy. Cabazitaxel, a new-generation antitubulin chemotherapeutic, and the radionuclide radium-223 chloride have also been shown to prolong survival. The biological agent cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against Met and vascular endothelial growth factor receptor 2, demonstrated promising results in a phase II trial and is currently being assessed in two large randomized phase 3 controlled trials.. This recent progress is unprecedented and has already translated to a significant increase in the available armamentarium of drugs for mCRPC. Nonetheless, there are still significant unresolved questions as to the proper sequencing of these novel drugs along the disease continuum. Moreover, the problem of drug resistance, either primary of acquired, continues to be a major therapeutic obstacle.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Anilides; Antineoplastic Agents; Benzamides; Humans; Male; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Pyridines; Quality of Life; Radioisotopes; Radium; Randomized Controlled Trials as Topic; Receptor Protein-Tyrosine Kinases; Taxoids

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

Patients with metastatic castration-resistant prostate cancer have few treatment options after novel hormonal therapy (eg, abiraterone or enzalutamide). We aimed to evaluate cabozantinib, a tyrosine kinase inhibitor with immunomodulatory properties, in combination with the PD-L1 inhibitor atezolizumab in metastatic castration-resistant prostate cancer.. COSMIC-021 is an ongoing, multicentre, open-label, phase 1b study with a dose-escalation stage followed by tumour-specific expansion stages. Expansion cohort 6 in metastatic castration-resistant prostate cancer was enrolled at 42 cancer research centres in France, Italy, the Netherlands, Spain, and the USA. Eligible patients were aged 18 years or older and had metastatic castration-resistant prostate cancer with radiographic soft tissue progression following treatment with either enzalutamide or abiraterone, or both; measurable soft tissue disease per Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1; and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received oral cabozantinib 40 mg per day and intravenous atezolizumab 1200 mg once every 3 weeks. Study treatment continued until progressive disease or unacceptable toxicity. All enrolled patients were assessed for efficacy and safety. The primary endpoint was objective response rate per RECIST version 1.1 as assessed by the investigator. This study is registered with ClinicalTrials.gov, NCT03170960.. Between April 24, 2018, and Aug 31, 2020, 132 patients were enrolled and received at least one dose of study treatment. At data cutoff (Feb 19, 2021), median duration of follow-up was 15·2 months (IQR 9·6-21·7). Objective response rate was 23% (95% CI 17-32; 31 of 132 patients), with three (2%) confirmed complete responses and 28 (21%) confirmed partial responses. 72 (55%) of 132 patients had grade 3-4 treatment-related adverse events, with the most common being pulmonary embolism (11 [8%] patients), diarrhoea (nine [7%]), fatigue (nine [7%]), and hypertension (nine [7%]). There was one grade 5 treatment-related adverse event (dehydration). 74 (56%) of 132 patients had serious adverse events of any causality. 28 (21%) of 132 patients had treatment-related adverse events leading to discontinuation of either study drug.. Cabozantinib plus atezolizumab showed promising antitumour activity in patients with metastatic castration-resistant prostate cancer after novel hormonal therapy with an acceptable safety profile, supporting further evaluation of this combination.. Exelixis.

Topics: Anilides; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Pyridines

To evaluate the safety and efficacy of cabozantinib combined with docetaxel.. A total of 44 men with mCRPC were enrolled in this phase 1/2 trial. An MTD of 40 mg cabozantinib plus docetaxel/prednisone was determined. Dose-limiting toxicities were neutropenic fever and palmar-plantar erythrodysesthesia, and there was one death attributable to a thromboembolic event. In addition, grade 3 or 4 myelosuppression, hypophosphataemia and neuropathy were seen in three or more patients. In the phase 1 study, the median time to progression (TTP) and overall survival (OS) time were 13.6 and 16.3 months, respectively. In the phase 2 study, which was terminated early because of poor accrual, the median TTP and OS favoured the combination (n = 13) compared to docetaxel/prednisone alone (n = 12; 21.0 vs 6.6 months; P = 0.035 and 23.8 vs 15.6 months; P = 0.072, respectively).. Despite the limited number of patients in this study, preliminary data suggest that cabozantinib can be safely added to docetaxel/prednisone with possible enhanced efficacy.

Topics: Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Humans; Male; Middle Aged; Neoplasm Metastasis; Prednisone; Prostatic Neoplasms, Castration-Resistant; Pyridines; Treatment Outcome

Scant evidence reveals whether the use of weekly versus daily pain ratings leads to meaningful differences when measuring pain as a clinical trial outcome. We compared the ability of weekly ratings and descriptors of daily ratings to evaluate pain as an endpoint in a randomized phase 3 drug trial.. Participants (. Use of daily over weekly ratings delivered no added benefit in evaluating pain in this clinical trial. This study is the first to compare weekly and daily recall to measure pain as an endpoint in a randomized phase 3 drug trial, and the pattern of differences in ratings that we observed is consistent with other recent evaluations of weekly and daily symptom reporting.

Topics: Anilides; Humans; Male; Pain; Pain Measurement; Prostatic Neoplasms, Castration-Resistant; Pyridines; Treatment Outcome

Two phase 3 trials, COMET-1 and COMET-2, have reported that cabozantinib did not significantly extend overall survival (OS) compared to prednisone and prednisone plus mitoxantrone, respectively, in post-docetaxel patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted a retrospective analysis of a combined data set from these trials to identify a benefit in subsets of patients according to prognostic risk factors. The prognostic ability of factors to predict survival was evaluated using Cox proportional hazards regression models. Evaluation of potential beneficial subsets was performed using interaction terms between factors and cabozantinib. All tests were two-sided and p≤0.05 was considered statistically significant. A total of 1147 post-docetaxel patients with mCRPC were available (1028 from COMET-1 and 119 from COMET-2). The following factors were prognostic for OS: age, disease-free interval, hemoglobin, prostate-specific antigen, alkaline phosphatase, albumin, bone scan lesion area, lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, and pain (all p<0.05). There was no interaction effect on survival between cabozantinib versus comparator arms and any prognostic group. After adjusting for prognostic factors, cabozantinib was associated with better OS (hazard ratio 0.80, 95% confidence interval 0.67-0.95; p=0.012). Further investigation of cabozantinib in a better-powered trial or a rational patient population based on a molecular biomarker may be warranted. PATIENT SUMMARY: Two phase 3 trials have reported no survival benefit for cabozantinib, a multitarget oral drug, in metastatic castration-resistant prostate cancer. This analysis pooled 1147 patients from these trials to identify a survival benefit for cabozantinib. This study suggests that further rational development may be justified.

Topics: Anilides; Antineoplastic Agents; Disease Progression; Docetaxel; Humans; Male; Prognosis; Prostatic Neoplasms, Castration-Resistant; Pyridines; Retrospective Studies; Risk Factors; Survival Rate

Cabozantinib, an oral inhibitor of c-MET/VEGFR2 signaling, improved progression-free survival (mPFS) but not overall survival (OS) in metastatic castrate-resistant prostate cancer. We evaluated cabozantinib plus androgen deprivation therapy (ADT) in hormone-naïve metastatic prostate cancer (HNMPCa).. Patients received ADT plus cabozantinib starting at 60 mg daily. The primary endpoint was castrate-resistant PFS by radiographic criteria, clinical progression, or receipt of additional therapy. Secondary endpoints included OS, safety, radiographic responses, and biomarker modulation.. Sixty-two patients received treatment. With a median follow-up of 31.2 months, the mPFS was 16.1 months (95% CI, 14.6-22.7 months), and mOS was not reached. Reductions in PSA ≥ 90%, bone-specific alkaline phosphatase ≥ 50%, and urine N-telopeptides ≥ 50% occurred in 83%, 87%, and 86% of evaluable patients, respectively. Responses in bone scan and measurable disease were observed in 81% of and 90% of evaluable patients, respectively. Most common grade 3 adverse events were hypertension (19%), diarrhea (6%), and thromboembolic events (6%), and dose reductions occurred in 85% of patients. Analysis of baseline cytokine and angiogenic factors (CAFs) revealed that higher plasma concentrations of Lumican, CXCL5, CD25, and CD30 were associated with shorter PFS as was high tumor expression of pFGFR1.. Cabozantinib plus ADT has promising clinical activity in HNMPCa. CAF profiles and tissue markers suggest candidate prognostic and predictive markers of cabozantinib benefit and provide insights for rational therapy combinations.

Topics: Aged; Aged, 80 and over; Androgen Antagonists; Anilides; Biomarkers, Tumor; Bone Neoplasms; Drug Therapy, Combination; Humans; Male; Middle Aged; Prognosis; Prostatic Neoplasms, Castration-Resistant; Pyridines; Survival Rate

Cabozantinib is active in advanced prostate cancer with improvement on bone scans in men on phase II trials. This trial evaluated the efficacy and changes in bone lesions in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabozantinib.. Eligible patients with mCRPC involving bone underwent biopsy of a bone lesion followed by cabozantinib starting at 60 mg daily and continuing until progression or intolerable toxicity. The primary study endpoint was progression-free survival at 12 weeks. The bone lesion was rebiopsied at 6 weeks. Expression of CMET, phospho-CMET, and VEGFR2 was assayed by immunohistochemistry. Serum was obtained at baseline, and at 3, 6, and 12 weeks and assayed for bone remodeling markers.. A total of 25 patients were enrolled: 22 were evaluable, and 3 were excluded before receiving cabozantinib. At 12 weeks, 17 (77%) of 22 patients had stable disease or better. The median time on treatment was 24 weeks (range, 3-112 weeks). The overall median progression-free survival was 43.7 weeks (95% confidence interval, 23.7-97.0 weeks). Eight (36%) of 22 patients had markedly reduced uptake on bone scan. Patients with significant response on bone scan had higher bone morphogenic protein-2 levels at baseline, stable N-telopeptides levels, increased vascular endothelial growth factor receptor 2 expression, and a trend towards increased phospho-CMET while on cabozantinib compared with patients with stable disease.. Cabozantinib is active in men with mCRPC, inducing significant changes on bone scan in one-third of patients with changes in markers of bone formation and the tumor microenvironment.

Topics: Aged; Anilides; Bone Neoplasms; Follow-Up Studies; Humans; Longitudinal Studies; Male; Middle Aged; Non-Randomized Controlled Trials as Topic; Prognosis; Prostatic Neoplasms, Castration-Resistant; Pyridines; Survival Rate

Bone metastases in patients with metastatic castration-resistant prostate cancer (mCRPC) are associated with debilitating pain and functional compromise.. To compare pain palliation as the primary endpoint for cabozantinib versus mitoxantrone-prednisone in men with mCRPC and symptomatic bone metastases using patient-reported outcome measures.. A randomized, double-blind phase 3 trial (COMET-2; NCT01522443) in men with mCRPC and narcotic-dependent pain from bone metastases who had progressed after treatment with docetaxel and either abiraterone or enzalutamide.. Cabozantinib 60mg once daily orally versus mitoxantrone 12mg/m. The primary endpoint was pain response at week 6 confirmed at week 12 (≥30% decrease from baseline in patient-reported average daily worst pain score via the Brief Pain Inventory without increased narcotic use). The planned sample size was 246 to achieve ≥90% power.. Enrollment was terminated early because cabozantinib did not demonstrate a survival benefit in the companion COMET-1 trial. At study closure, 119 participants were randomized (cabozantinib: N=61; mitoxantrone-prednisone: N=58). Complete pain and narcotic use data were available at baseline, week 6, and week 12 for 73/106 (69%) patients. There was no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone: the proportions of responders were 15% versus 17%, a -2% difference (95% confidence interval: -16% to 11%, p=0.8). Barriers to accrual included pretreatment requirements for a washout period of prior anticancer therapy and a narcotic optimization period to maximize analgesic dosing.. Cabozantinib treatment did not demonstrate better pain palliation than mitoxantrone-prednisone in heavily pretreated patients with mCRPC and symptomatic bone metastases. Future pain-palliation trials should incorporate briefer timelines from enrollment to treatment initiation.. Cabozantinib was not better than mitoxantrone-prednisone for pain relief in patients with castration-resistant prostate cancer and debilitating pain from bone metastases.

Topics: Aged; Analgesics; Anilides; Bone Neoplasms; Cancer Pain; Double-Blind Method; Drug Combinations; Humans; Male; Middle Aged; Mitoxantrone; Pain Management; Pain Measurement; Prednisone; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Pyridines

Cabozantinib is an orally available inhibitor of tyrosine kinases including VEGFR2 and c-MET. We performed a post hoc analysis to find associations between select plasma biomarkers and treatment response in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) who received cabozantinib 100 mg daily as part of a phase 2 non-randomized expansion cohort (NCT00940225).. Plasma samples were collected at baseline, 6 weeks and at time of maximal response from 81 mCRPC pts with bone metastases, of which 33 also had measurable soft-tissue disease. Levels of 27 biomarkers were measured in duplicate using enzyme-linked immunosorbent assay. Spearman correlation coefficients were calculated for the association between biomarker levels or their change on treatment and either bone scan response (BSR) or soft tissue response according to RECIST.. A BSR and RECIST response were seen in 66/81 pts (81 %) and 6/33 pts (18 %) respectively. No significant associations were found between any biomarker at any time point and either type of response. Plasma concentrations of VEGFA, FLT3L, c-MET, AXL, Gas6A, bone-specific alkaline phosphatase, interleukin-8 and the hypoxia markers CA9 and clusterin significantly increased during treatment with cabozantinib irrespective of response. The plasma concentrations of VEGFR2, Trap5b, Angiopoietin-2, TIMP-2 and TIE-2 significantly decreased during treatment with caboznatinib.. Our data did not reveal plasma biomarkers associated with response to cabozantinib. The observed alterations in several biomarkers during treatment with cabozantinib may provide insights on the effects of cabozantinib on tumor cells and on tumor micro-environment and may help point to potential co-targeting approaches.

Topics: Anilides; Biomarkers, Tumor; Humans; Male; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Pyridines; Reproducibility of Results; Statistics, Nonparametric

Cabozantinib is an inhibitor of kinases, including MET and vascular endothelial growth factor receptors, and has shown activity in men with previously treated metastatic castration-resistant prostate cancer (mCRPC). This blinded phase III trial compared cabozantinib with prednisone in patients with mCRPC.. Men with progressive mCRPC after docetaxel and abiraterone and/or enzalutamide were randomly assigned at a two-to-one ratio to cabozantinib 60 mg once per day or prednisone 5 mg twice per day. The primary end point was overall survival (OS). Bone scan response (BSR) at week 12 as assessed by independent review committee was the secondary end point; radiographic progression-free survival (rPFS) and effects on circulating tumor cells (CTCs), bone biomarkers, serum prostate-specific antigen (PSA), and symptomatic skeletal events (SSEs) were exploratory assessments.. A total of 1,028 patients were randomly assigned to cabozantinib (n = 682) or prednisone (n = 346). Median OS was 11.0 months with cabozantinib and 9.8 months with prednisone (hazard ratio, 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = .213). BSR at week 12 favored cabozantinib (42% v 3%; stratified Cochran-Mantel-Haenszel P < .001). rPFS was improved in the cabozantinib group (median, 5.6 v 2.8 months; hazard ratio, 0.48; 95% CI, 0.40 to 0.57; stratified log-rank P < .001). Cabozantinib was associated with improvements in CTC conversion, bone biomarkers, and post-random assignment incidence of SSEs but not PSA outcomes. Grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone (71% v 56% and 33% v 12%, respectively).. Cabozantinib did not significantly improve OS compared with prednisone in heavily treated patients with mCRPC and progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving BSR, rPFS, SSEs, CTC conversions, and bone biomarkers but not PSA outcomes.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Antineoplastic Agents; Biomarkers, Tumor; Disease-Free Survival; Double-Blind Method; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prednisone; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines; Survival Rate

Pain negatively affects quality of life for cancer patients. Preliminary data in metastatic castration-resistant prostate cancer (mCRPC) suggested a benefit of the oral tyrosine kinase inhibitor cabozantinib to pain palliation.. Prospective evaluation of cabozantinib's benefits on pain and narcotic use in mCRPC.. This was a nonrandomized expansion (NRE) cohort (n=144) of a phase 2 randomized discontinuation trial in docetaxel-refractory mCRPC patients. Pain and interference of symptoms with sleep and general activity were electronically self-reported daily for 7-d intervals at baseline and regularly scheduled throughout the study. Mean per-patient scores were calculated for each interval. Narcotic use was recorded daily during the same intervals.. Open-label cabozantinib (100mg or 40mg).. The following stringent response definition was used: clinically meaningful pain reduction (≥30% improvement in mean scores from baseline) confirmed at a later interval without concomitant increases in narcotics. Only patients with moderate or severe baseline pain were analyzed.. Sixty-five patients with moderate or severe baseline pain were evaluable. Of these, 27 (42%) experienced pain palliation according to the stringent response definition. Thirty-seven patients (57%) had clinically meaningful pain relief at two consecutive intervals, reported ≥6 wk apart in the majority. Forty-four patients (68%) had palliation at one or more intervals; 36 (55%) decreased narcotics use during one or more intervals. Clinically meaningful pain reduction was associated with significant (p ≤ 0.001) improvements in sleep quality and general activity. A limitation of this study was its open-label design.. Cabozantinib demonstrated clinically meaningful pain palliation, reduced or eliminated patients' narcotic use, and improved patient functioning, thus meriting prospective validation in phase 3 studies.. We evaluated the potential of cabozantinib to improve symptoms in patients with metastatic prostate cancer that no longer responds to standard therapies. We saw a promising reduction in pain and reduced need for narcotic painkillers. Larger, well-controlled trials are necessary to confirm these findings.

Topics: Aged; Analgesics, Opioid; Anilides; Antineoplastic Agents; Humans; Male; Middle Aged; Pain; Pain Measurement; Palliative Care; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines; Severity of Illness Index; Time Factors; Treatment Outcome; United Kingdom; United States

Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC).. Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers.. One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group.. The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.

Topics: Adult; Aged; Aged, 80 and over; Anilides; Bone and Bones; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplastic Cells, Circulating; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines; Radionuclide Imaging; Receptor Protein-Tyrosine Kinases

Cabozantinib is a multitargeted tyrosine kinase inhibitor that demonstrated remarkable responses on bone scan in metastatic prostate cancer. Randomized trials failed to demonstrate statistically significant overall survival (OS). We studied the dynamics of biomarker changes with imaging and biopsies pretherapy and posttherapy to explore factors that are likely to be predictive of efficacy with cabozantinib.. Early changes in imaging and tissue or serum/urine biomarkers did not demonstrate utility in predicting clinical benefit with cabozantinib therapy.

Topics: Aged; Anilides; Biomarkers, Tumor; Biopsy; Bone and Bones; Bone Neoplasms; Disease Management; Humans; Image Processing, Computer-Assisted; Kallikreins; Male; Middle Aged; Models, Biological; Molecular Targeted Therapy; Positron-Emission Tomography; Prognosis; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines; Treatment Outcome

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.

Topics: Aged; Anilides; Cyclin-Dependent Kinases; Enhancer Elements, Genetic; Gene Duplication; Gene Rearrangement; Genes, myc; Genetic Loci; Haplotypes; Humans; Male; Middle Aged; Neoplasm Metastasis; Phenotype; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Pyridines; Receptors, Androgen; Whole Genome Sequencing

Topics: Anilides; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Male; Patient Selection; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Pyridines

A significant fraction of patients with advanced prostate cancer treated with androgen deprivation therapy experience relapse with relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). Immune checkpoint blockade using antibodies against cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed cell death 1 ligand 1 (PD1/PD-L1) generates durable therapeutic responses in a significant subset of patients across a variety of cancer types. However, mCRPC showed overwhelming de novo resistance to immune checkpoint blockade, motivating a search for targeted therapies that overcome this resistance. Myeloid-derived suppressor cells (MDSCs) are known to play important roles in tumour immune evasion. The abundance of circulating MDSCs correlates with prostate-specific antigen levels and metastasis in patients with prostate cancer. Mouse models of prostate cancer show that MDSCs (CD11b

Topics: Anilides; Animals; CD8-Positive T-Lymphocytes; Chimera; Cytokines; Disease Models, Animal; Drug Synergism; Female; Humans; Imidazoles; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Male; Mice; Molecular Targeted Therapy; Myeloid-Derived Suppressor Cells; Phosphoinositide-3 Kinase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Pyridines; Quinolines; Signal Transduction; Tumor Microenvironment

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most men with CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation of MET by AR signaling, we hypothesized that intact AR signaling may have limited the efficacy of cabozantinib in some of these patients. To assess the role of AR signaling on MET inhibition, we first performed an in silico analysis of human CRPC tissue samples stratified by AR signaling status ((+) or (-)), which identified MET expression as markedly increased in AR(-) samples. In vitro, AR signaling inhibition in AR(+) CRPC models increased MET expression and resulted in susceptibility to ligand (HGF) activation. Likewise, MET inhibition was only effective in blocking cancer phenotypes in cells with MET overexpression. Using multiple AR(+) CRPC in vitro and in vivo models, we showed that combined cabozantinib and enzalutamide (AR antagonist) treatment was more efficacious than either inhibitor alone. These data provide a compelling rationale to combine AR and MET inhibition in CRPC and may explain the negative results of the phase III cabozantinib study in CRPC. Similarly, the expression of MET in AR(-) disease, whether due to AR inhibition or loss of AR signaling, suggests potential utility for MET inhibition in select patients with AR therapy resistance and in AR(-) prostate cancer.

Topics: Androgen Receptor Antagonists; Anilides; Animals; Antineoplastic Agents; Benzamides; Cell Line, Tumor; Cell Survival; Cluster Analysis; Disease Models, Animal; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Male; Mice; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays

MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6% of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named MET(Δ7-8). MET(Δ7-8) is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET(Δ7-8), in combination with a lack of transmembrane localization, renders MET(Δ7-8) not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making.

Topics: Anilides; Animals; Antibodies; Carcinoma; Cell Line, Tumor; Female; Glioma; Hepatocyte Growth Factor; Humans; Male; Mice; Neoplasm Grading; Neoplasm Transplantation; Prostatic Neoplasms, Castration-Resistant; Protein Conformation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; RNA, Messenger; Sarcoma; Sequence Deletion

Topics: Anilides; Clinical Trials as Topic; Humans; Male; Pain; Prostatic Neoplasms, Castration-Resistant; Pyridines; Receptor Protein-Tyrosine Kinases

Prostate cancer is incurable once it has metastasized to the bone. Appropriate preclinical models are lacking. The therapeutic efficacy of the multikinase inhibitor cabozantinib was assessed in an orthotopic xenograft model of castration-resistant prostate cancer (CRPC) bone metastasis using noninvasive, multimodality functional imaging.. NOD/SCID mice were injected intratibially with luciferase-expressing ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) rearranged VCaP human prostate carcinoma cells. The response of VCaP xenografts (n = 7 per group) to cabozantinib was investigated using bioluminescence imaging and anatomical and diffusion weighted magnetic resonance imaging. This enabled quantitation of tumor volume and apparent diffusion coefficient (ADC). Bone uptake of technetium-methylene diphosphonate ((99m)Tc-MDP) was assessed by single-photon emission computed tomography. Ex vivo micro computed tomography was used to quantify bone volume and correlated with appropriate histopathology. Statistical significance was determined using the two-sided Mann-Whitney test or Wilcoxon signed rank test.. VCaP xenografts were predominantly osteosclerotic with some osteolytic activity. Fluorescent in situ hybridization analysis confirmed retention of ERG oncogene rearrangements. Cabozantinib induced a statistically significant 52% reduction in tumor luminance (P = .02) and stasis in tumor volume after 15 days of treatment. Tumor ADC statistically significantly increased with cabozantinib and was associated with extensive necrosis (after 10 days, mean tumor ADC ± SD = 556±43×10(-6) mm(2)/s vs pretreatment ADC = 485±43×10(-6) mm(2)/s; P = .02 ). Tumor-associated uptake of (99m)Tc-MDP was statistically significantly reduced after 3 days of treatment (P = .02), sustained over 15 days treatment, and associated with a statistically significant (P = .048) reduction in bone growth on the tibial cortex, yet a highly statistically significant (P = .001) increase in trabecular bone volume.. The intratibial VCaP model faithfully emulates clinical disease. Cabozantinib exerts potent effects on both tumor and tumor-induced bone matrix remodeling, and quantitation of ADC provides a clinically translatable imaging biomarker for early, sensitive assessment of treatment response in CRPC bone metastasis.

Topics: Aged; Anilides; Animals; Antineoplastic Agents; Biomarkers, Tumor; Bone Neoplasms; Bone Remodeling; Diffusion Magnetic Resonance Imaging; Humans; Luminescent Measurements; Male; Mice; Mice, Inbred NOD; Mice, Nude; Middle Aged; Osteolysis; Osteosclerosis; Prostatic Neoplasms, Castration-Resistant; Pyridines; Radiopharmaceuticals; Receptor Protein-Tyrosine Kinases; Technetium Tc 99m Medronate; Tomography, Emission-Computed, Single-Photon; 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

Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.

Topics: Androgens; Anilides; Animals; Body Weight; Bone Remodeling; Cell Line, Tumor; Cell Proliferation; Humans; Male; Mice; Phosphoproteins; Prostatic Neoplasms, Castration-Resistant; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyridines; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays