Abstract Metastatic involvement of the viscera in men with advanced castration-resistant prostate cancer (CRPC) has been poorly characterised to date. In 359 CRPC patients treated between June 2003 ...and December 2011, the frequency of radiologically detected visceral metastases before death was 32%. Of the 92 patients with computed tomography performed within 3 mo of death, 49% had visceral metastases. Visceral metastases most commonly involved the liver (20%) and lung (13%). Median survival from diagnosis of visceral disease was 7.1 mo (95% confidence interval, 5.9–8.3). Survival was affected by the degree of bone involvement at detection of visceral disease, varying from 6.1 mo in men with more than six bone metastases to 18.2 mo in men with no bone metastases ( p = 0.001). Heterogeneity was noted in clinical phenotypes and prostate-specific antigen trends at development of visceral metastases. Visceral metastases are now more commonly detected in men with CRPC, likely due to the introduction of novel survival-prolonging treatments.
Background
CC‐90011 is an oral, potent, selective, reversible inhibitor of lysine‐specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid ...tumors or relapsed/refractory marginal zone lymphoma. The authors present long‐term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first‐in‐human study of CC‐90011.
Methods
CC‐90011‐ST‐001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243‐13) is a phase 1, multicenter study in which patients received CC‐90011 once per week in 28‐day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary).
Results
Sixty‐nine patients were enrolled, including 50 in the dose‐escalation arm and 19 in the dose‐expansion arm. Thrombocytopenia was the most common treatment‐related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose‐escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose‐expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC‐90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin‐releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte‐to‐macrophage differentiation–associated.
Conclusions
The safety profile of CC‐90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once‐per‐week dosing support further exploration of CC‐90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies.
This first‐in‐human study evaluated CC‐90011, a highly potent, selective, and reversible oral lysine‐specific demethylase 1 inhibitor, in patients with advanced solid tumors and relapsed/refractory lymphoma. The tolerability, clinical activity, and once‐weekly dosing support further exploration of CC‐90011 in patients with advanced malignancies.
Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple ...prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed
by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth
and
. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide-resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. SIGNIFICANCE: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to second-generation antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.
: Detection of androgen receptor (AR) splice variant-7 (AR-V7) messenger RNA (mRNA) in circulating tumor cells (CTCs) is associated with a suboptimal response to abiraterone and enzalutamide in ...metastatic castration-resistant prostate cancer (mCRPC). Galeterone inhibits CYP17 and AR, and induces AR protein degradation. We hypothesized that galeterone would be clinically superior to enzalutamide in AR-V7–positive (AR-V7+) mCRPC.
: To screen and characterize AR-V7+ mCRPC, and evaluate galeterone compared with enzalutamide.
: This was a multicenter randomized phase 3 trial; enzalutamide-, abiraterone-, and chemotherapy-naïve mCRPC patients had AR-V7 prescreening using a CTC-based mRNA assay.
: AR-V7+ patients were randomized (1:1) to open-label galeterone or enzalutamide; planned sample size was 148.
: The primary endpoint was radiographic progression-free survival (rPFS). Baseline AR-V7 status was correlated with patient characteristics.
: Overall, 953 men were prescreened for AR-V7; 323 (34%) had detectable CTCs, and 73/323 had AR-V7 mRNA. The AR-V7+ prevalence was 8% (73/953; 95% confidence interval CI 6–10%). AR-V7 was associated with indicators of advanced and high-volume disease at baseline, including higher prostate-specific antigen (PSA) level (p < 0.001), more bone metastases (p < 0.001), docetaxel for hormone-sensitive disease (p < 0.001), prior first-generation androgen deprivation therapy (p < 0.001), and shorter time from diagnosis to enrollment (p < 0.001). Of 73 eligible patients, 38 were randomized to galeterone (n=19) or enzalutamide (n=19); 35 dropped out before randomization. Owing to high censorship for the rPFS events, the data monitoring committee recommended early closure based on interim evidence that the primary endpoint would not be met. The PSA50 values were 2/16 (13%) and 8/19 (42%) for galeterone and enzalutamide respectively (proportion difference=−0.278, 95% CI −0.490 to 0.097).
: The prevalence of CTC mRNA AR-V7 in first-line mCRPC was 8% (95% CI 6–10%). AR-V7+ was associated with the characteristics of aggressive and advanced disease. These men had rapid disease progression. Development of galeterone will not be pursued.
: Of men with metastatic castration-resistant prostate cancer, 8% had the androgen receptor splice variant-7 (AR-V7) blood biomarker. The AR-V7+ patients had features of aggressive disease. Thirty-eight men were treated with either galeterone or enzalutamide; the trial was stopped early prior to determining efficacy because too many patients transitioned off the trial due to advancing cancer before having required radiographs.
The prevalence of circulating tumor cells expressing androgen receptor V7 in castration-resistant prostate cancer naïve to abiraterone or enzalutamide is low and associated with aggressive disease. Treatment approaches other than available second-generation androgen axis inhibitors should be considered.
Abstract Background The androgen receptor splice variant-7 (AR-V7) has been implicated in the development of castration-resistant prostate cancer (CRPC) and resistance to abiraterone and ...enzalutamide. Objective To develop a validated assay for detection of AR-V7 protein in tumour tissue and determine its expression and clinical significance as patients progress from hormone-sensitive prostate cancer (HSPC) to CRPC. Design, setting, and participants Following monoclonal antibody generation and validation, we retrospectively identified patients who had HSPC and CRPC tissue available for AR-V7 immunohistochemical (IHC) analysis. Outcome measurements and statistical analysis Nuclear AR-V7 expression was determined using IHC H score (HS) data. The change in nuclear AR-V7 expression from HSPC to CRPC and the association between nuclear AR-V7 expression and overall survival (OS) was determined. Results and limitations Nuclear AR-V7 expression was significantly lower in HSPC (median HS 50, interquartile range IQR 17.5–90) compared to CRPC (HS 135, IQR 80–157.5; p < 0.0001), and in biopsy tissue taken before (HS 80, IQR 30–136.3) compared to after (HS 140, IQR 105–167.5; p = 0.007) abiraterone or enzalutamide treatment. Lower nuclear AR-V7 expression at CRPC biopsy was associated with longer OS (hazard ratio 1.012, 95% confidence interval 1.004–1.020; p = 0.003). While this monoclonal antibody primarily binds to AR-V7 in PC biopsy tissue, it may also bind to other proteins. Conclusions We provide the first evidence that nuclear AR-V7 expression increases with emerging CRPC and is prognostic for OS, unlike antibody staining for the AR N-terminal domain. These data indicate that AR-V7 is important in CRPC disease biology; agents targeting AR splice variants are needed to test this hypothesis and further improve patient outcome from CRPC. Patient summary In this study we found that levels of the protein AR-V7 were higher in patients with advanced prostate cancer. A higher level of AR-V7 identifies a group of patients who respond less well to certain prostate cancer treatments and live for a shorter period of time.
PI3K-Akt-mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We ...therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC.
Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1,000 mg orally. Coprimary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors.
rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths.
In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors.
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Circulating tumor cells (CTC) detected in the blood of cancer patients could be used for risk-stratification, molecular subclassification and as an intermediate end-point in therapeutic efficacy ...studies. Most studies to date have focused on enumeration of CTC in advanced cancer patients but further development of CTC evaluation technologies could allow expansion into early disease, monitoring of treatment response, and selection of patients for targeted therapies based on a CTC derived signature. This review discusses the challenges faced in achieving these goals, including the potential absence of CTC in patients with no blood-borne metastases, CTC intra-patient molecular heterogeneity, ex vivo loss of CTC viability, and the biological differences between CTC and metastatic tissue.
Recent data report that abiraterone acetate, a specific inhibitor of CYP17 that is key to androgen and estrogen synthesis, improves survival in metastatic castration-resistant prostate cancer (CRPC), ...confirming the continued dependency of CRPC on the androgen receptor (AR) signaling pathway. MDV3100 is a novel antagonist of AR that is also in phase III clinical trials. In addition, several other agents targeting the AR axis are undergoing evaluation in early clinical studies. CRPC patients progress on these therapies with an increasing prostate specific antigen (PSA), suggesting that repeated therapeutic interventions targeting the AR signaling axis could induce secondary responses and achieve prolonged clinical benefit for a subgroup of patients. These exciting results are good news for patients but introduce a number of treatment paradigm dilemmas for physicians. Clinical studies evaluating the ideal sequence of administration of these new agents, best timing for initiation, combination strategies, discontinuation beyond progression and after commencement of subsequent therapies, and coordination with other treatments have not been done. Predictive biomarkers could allow patient selection for a specific treatment, but in their absence, most physicians will rely on a trial of treatment with a preferred agent and substitute for an alternative therapy on objective progression. Current data suggest that the response rate to drugs targeting the AR ligand-binding domain decreases with each treatment, but we hypothesize that a significant proportion of CRPC remains dependent on the AR axis and, therefore, novel strategies for disrupting AR signaling merit evaluation.
Summary Background Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that ...induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. Methods In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov , NCT00749502. Findings Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients 48%), nausea (42 42%), fatigue (42 42%), thrombocytopenia (35 35%), anorexia (26 26%), neutropenia (24 24%), constipation (23 23%), and vomiting (20 20%), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8–46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% 95% CI 19–64) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% 7–93) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. Interpretation A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. Funding Merck Sharp and Dohme.
Prostate cancer is the second leading cause of male cancer deaths. Castration-resistant prostate cancer (CRPC) is a lethal stage of the disease that emerges when endocrine therapies are no longer ...effective at suppressing activity of the androgen receptor (AR) transcription factor. The purpose of this study was to identify genomic mechanisms that contribute to the development and progression of CRPC.
We used whole-genome and targeted DNA-sequencing approaches to identify mechanisms underlying CRPC in an aggregate cohort of 272 prostate cancer patients. We analyzed structural rearrangements at the genome-wide level and carried out a detailed structural rearrangement analysis of the
locus. We used genome engineering to perform experimental modeling of
gene rearrangements and long-read RNA sequencing to analyze effects on expression of AR and truncated AR variants (AR-V).
was among the most frequently rearranged genes in CRPC tumors.
gene rearrangements promoted expression of diverse AR-V species.
gene rearrangements occurring in the context of
amplification correlated with AR overexpression. Cell lines with experimentally derived
gene rearrangements displayed high expression of tumor-specific AR-Vs and were resistant to endocrine therapies, including the AR antagonist enzalutamide.
gene rearrangements are an important mechanism of resistance to endocrine therapies in CRPC.
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