Fig 1 - uploaded by Anil Kapoor
Content may be subject to copyright.
Treatment options for localized and metastatic prostate cancer and the sites of action of agents used to treat metastatic castration-resistant prostate cancer. LH: luteinizing hormone; LHRH: luteinizing hormone-releasing hormone.
Source publication
Docetaxel-based chemotherapy has been the standard of care for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Over the past few years, there has been a significant paradigm shift in the treatment landscape of this disease. A deeper understanding of prostate cancer biology, along with the development of novel agents has created...
Contexts in source publication
Context 1
... especially with known cross- resistance among these novel agents. [22][23][24] This article will review the current literature on the treatment of mCRPC with special focus on immunotherapies, novel chemotherapeutic agents, hormonal therapies, and radiopharmaceuticals. A better understanding of the mechanisms and sites of action of these therapies (Fig. 1) will better assist physicians in making informed therapeutic decisions. This is of increasing importance, as there is paucity of data on the sequence of administration of these agents in the treatment of ...
Context 2
... (Fig. 2). 39 The inhibition of 17α-hydroxylase activity dramatically reduces the pro- duction of cortisol, with low serum cortisol levels stimulating a cortisol-adrenocorticotropic hormone (ACTH) feedback loop, leading to increased serum ACTH release from the pituitary gland and subsequent excessive mineralocorticoid (aldosterone) production (Fig. 1). This clinically manifests as fluid overload, hypokalemia, renin suppression, and arte- rial hypertension, 40 necessitating low-dose glucocorticoid supplementation along with CYP17 inhibitor ...
Context 3
... acetate (AA) is the prodrug of abiraterone, an irreversible, highly selective CYP17 inhibitor that targets its 17α-hydroxylase and C 17,20 -lyase activities (Fig. 2), 41 resulting in reduced testosterone production in adrenal, testicular, and prostate tumours (Fig. 1). 42 The safety, efficacy, and tolerabil- ity of AA were demonstrated in phase ½ trials administered either alone or with oral prednisone, with significant anti- tumour activity being reported in mCRPC patients who had previously received chemotherapy, such as docetaxel, and in those patients who were chemotherapy-naïve. ...
Similar publications
Background
The objective of this study was to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in patients with taxane-refractory metastatic castrate-resistant prostate cancer (mCRPC) and evaluate utility of this metric in informing int...
The number of treatment options for metastatic hormone-sensitive prostate cancer has increased substantially in recent years. The classic treatment approach for these patients-androgen-deprivation therapy alone-is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits-including signif...
More than 90 % of patients with metastatic castration-resistant prostate cancer (CRPC) have radiologically confirmed skeletal metastases. Traditional treatment methods such as administration of painkillers, external beam therapy, bisphosphonates or denosumab, as well as injections of strontium-89 or samarium-153 radionuclides, have only palliative...
Purpose
To evaluate the potential benefit of curative radiotherapy (RT) to the primary tumor in metastatic castration-resistant prostate cancer (mCRPC) patients treated with abiraterone.
Materials and methods
The clinical parameters of 106 mCRPC patients treated with abiraterone were retrospectively evaluated. Patients were either oligometastatic...
This study investigated the clinical activity of abiraterone plus prednisone in docetaxel-naïve and docetaxel-resistant Chinese patients with metastatic castration-resistant prostate cancer (mCRPC). A total of 146 patients with docetaxel-naïve group (103 cases) and docetaxel-resistant group (43 cases) were enrolled from the Shanghai Cancer Center (...
Citations
... Most of the early-stage PCa patients who have been treated with ADT show good initial responses. However, a vast majority of men with early-stage PCa eventually become unresponsive to these primary treatment options, and despite low levels of androgen, the disease progresses with continuously rising Prostate Serum Antigen (PSA), ultimately developing more aggressive forms called Castration-resistant prostate cancer (CRPC) [7][8][9][10]. Metastatic castration-resistant prostate cancer (mCRPC) is the clinically most advanced and lethal disease state with signs of metastasis to distant organs like the brain, bone, lung, and lymph nodes and it has a median survival of fewer than three years (5-year median survival rate of 31%) [11,12]. ...
Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) is nearly universal. Further, the presence of cancer stem-like cells (EMT/epithelial-to-mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/lethal/advanced variants of PCa (AVPC). In this study, we introduced a pharmacogenomics data-driven optimization-regularization-based computational prediction algorithm (“secDrugs”) to predict novel drugs against lethal PCa. Integrating secDrug with single-cell RNA-sequencing/scRNAseq as a ‘Double-Hit’ drug screening tool, we demonstrated that single-cells representing drug-resistant and stem-cell-like cells showed high expression of the NAMPT pathway genes, indicating potential efficacy of the secDrug FK866 which targets NAMPT. Next, using several cell-based assays, we showed substantial impact of FK866 on clinically advanced PCa as a single agent and in combination with taxanes or AR-inhibitors. Bulk-RNAseq and scRNAseq revealed that, in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes, HES1 and CD44. Further, we combined a microfluidic chip-based cell migration assay with a traditional cell migration/‘scratch’ assay and demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using PCa patient datasets, we showed that FK866 is potentially capable of reversing the expression of several genes associated with biochemical recurrence, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept candidate for drug repurposing, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa.
... In line with this are the encouraging observations reported with immune checkpoint blockade in select subsets [3], as well as with the use of PARP inhibitors in cancers with DNA damage repair alterations [4,5]. However, despite the marked lengthening of overall survival (OS), cure rates in men with metastatic PCa remain low [6]. The long-term goal of therapy is to shift from the prevailing treatment paradigm to a curative paradigm. ...
The Hippo pathway regulates and contributes to several hallmarks of prostate cancer (PCa). Although the elucidation of YAP function in PCa is in its infancy, emerging studies have shed light on the role of aberrant Hippo pathway signaling in PCa development and progression. YAP overexpression and nuclear localization has been linked to poor prognosis and resistance to treatment, highlighting a therapeutic potential that may suggest innovative strategies to treat cancer. This review aimed to summarize available data on the biological function of the dysregulated Hippo pathway in PCa and identify knowledge gaps that need to be addressed for optimizing the development of YAP-targeted treatment strategies in patients likely to benefit.
... Most of the early-stage PCa patients who have been treated with ADT show good initial responses. However, a vast majority of men with early-stage PCa eventually become unresponsive to these primary treatment options, and despite low levels of androgen, the disease progresses with continuously rising Prostate Serum Antigen (PSA), ultimately developing more aggressive forms called Castration-resistant prostate cancer (CRPC) [7][8][9][10]. Metastatic castration-resistant prostate cancer (mCRPC) is the clinically most advanced and lethal disease state with signs of metastasis to distant organs like the brain, bone, lung, and lymph nodes and it has a median survival of fewer than three years (5-year median survival rate of 31%) [11,12]. ...
Metastatic prostate cancer is the second leading cause of cancer deaths in US men. Resistance to standard medical castration and secondary taxane-based chemotherapy is nearly universal. Further, presence of cancer stem-like cells (EMT/epithelial to mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/advanced/lethal variants of PCa (AVPC) .
In this study, first we used single-cell RNA sequencing (scRNAseq) analysis to demonstrate that AR low PCa cells in metastatic prostate cancer, including castration-sensitive tumors, harbored signatures of EMT, and ‘cancer stemness’. Next, we introduced a novel pharmacogenomics data-driven computational approach and identified several potential agents that can be re-purposed as novel secondary drugs (“secDrugs”) to treat advance variants of Prostate cancer. Using scRNAseq as a biomarker-based drug screen, we demonstrated that a majority of the single-cell subclones in mCRPC and mCSPC cell lines also showed significantly high expression of the NAMPT pathway genes, indicating that the secDrug FK866, which targets NAMPT, is potentially effective against drug-resistant and stem-cell-like subpopulation cluster. Next, we showed significant in vitro cytotoxicity of FK866 as single-agent and in combination with the taxanes or Enzalutamide against models of clinically-advanced PCa. We performed bulk- and single-cell RNAseq to identify several pathways underlining FK866 mechanism of action and found that in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes HES1 and CD44. Further, we performed a microfluidic chip-based cell migration assay that demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using multiple PCa patient datasets, we showed that FK866 is potentially capable of reversing expression of several genes associated with biochemical recurrence and inter-ethnic differences, including IFITM3 and LTB4R.
Thus, using FK866 as a proof-of-concept drug, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa.
... Cabazitaxel (Fig. 1B) is a tubulin-binding taxane agent with antitumor activity in docetaxel-resistant cancers approved by the Food and Drug Administration for use in the treatment of hormone-refractory prostate cancer. One of the major problems with conventional chemotherapy is the risk of tumor-initiating cells becoming drug resistant and recurrent of the disease by avoiding treatment [15]. Therefore, co-administration of chemotherapeutics such as cabazitaxel with agents that are selective to tumor-initiating cancer cells may increase antitumor efficacy, allow lower use of chemotherapy agents in treatment, thereby reducing drug resistance or lessen the side effects associated with chemotherapeutics. ...
Background
Tumor-initiating or cancer stem cells (CSCs) reduce the effectiveness of conventional therapy. Thus, it is crucial to eliminate CSCs while killing bulky cancer cells using a combination of conventional chemotherapy and anti-CSC drugs. Salinomycin is a selective inhibitor against CSCs and shows promise in combination applications. The aim of the study was to examine the efficacy of co-administered cabazitaxel and salinomycin on the survival of prostate cancer cells and CSCs.
Methods and Results
CD44 + stem cells were isolated from human PC3 prostate cancer cells by using magnetic activated cell sorting. The cells were concomitantly exposed to salinomycin and cabazitaxel, and the cell survival was determined by MTT test. Apoptosis was assessed by image-based cytometer, and cell migration was evaluated by wound healing assay. The expression of target mRNA and protein were assessed by RT-qPCR and Western blot, respectively. Combination index (CI) analysis showed that simultaneous administration of salinomycin and cabazitaxel was able to exert strong synergistic effect on CD44 + subpopulation (CI = 0.33), but no synergism was observed in PC3 cells. The combination of the two agents significantly increased Bax, cytochrome c, caspase-3 and − 8 mRNA expression in CD44 + CSCs, causing apoptosis. The applied therapy strategy strongly inhibited the phosphorylation of Akt, protein expression of Akt1, NF-κB and Wnt.
Conclusions
In conclusion, our data suggest that combining salinomycin with cabazitaxel shows promise as a prostate cancer treatment approach that can target CSCs.
... Another interesting finding is the apparent decrease in GnRH receptor turn-over rate that could be inferred from the testosterone dynamics for cycle two compared to cycle one. Five potential mechanisms leading to CRPC development have been suggested, including changes in transcription and/or testosterone receptor expression for which ADT may form a trigger [30]. A delay in the recovery phase of iADT following active treatment is a direct consequence of the observed change in GnRH-receptor dynamics. ...
Intermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in active and recovery phases allows inference of new information from this patient population. Efficacy of androgen deprivation therapy is presumed to depend on a treshold value for testosterone at the nadir, below which no additional beneficial effects on PSA reponse can be expected, and occurance of testosterone breakthroughs during active therapy. The present analysis results in a mixed effect model, incorporating GnRH receptor activation, testosterone turnover and feedback mechanisms, describing and predicting testosterone inhibition under intermittent androgen deprivation therapy on the individual and population level, during multiple years of therapy. Testosterone levels in these patients decline over time with an estimated first order rate constant of 0.083 year−1(T1/2 = 8.4 y), with a substantial distribution among this patient population, compared to the general population. PCa patients leaving the trial due to unmanageble PSA relapse appear to have slightly higher testosterone levels at the nadir than sustained responders. These findings are expected to contribute to an increased understanding of the role of testosterone in long term disease progression of prostate cancer.
... Despite a wide range of life-prolonging treatment options, the optimal therapeutic sequencing, timing, and combinations of treatments for mCRPC patients remain unclear [7]. This makes it important to consider the patient's health status and adverse events when selecting an appropriate drug. ...
Objectives
To investigate real‐world haematological toxicity, overall survival (OS) and the treatment characteristics of docetaxel and cabazitaxel chemotherapy in metastatic castration‐resistant prostate cancer (mCRPC).
Patients and Methods
This retrospective claims data study followed patients with mCRPC receiving cabazitaxel or docetaxel from their first chemotherapy infusion. Haematological toxicities were measured using treatment codes and inpatient diagnoses. OS was estimated using the Kaplan–Meier method. A multivariable Cox regression analysis was used to identify OS predictors.
Results
Data from 539 patients administered docetaxel and 240 administered cabazitaxel were analysed. Regarding adverse events, within 8 months of treatment initiation, some kind of treatment for haematological toxicity was documented in 31% of patients given docetaxel and in 61% of patients given cabazitaxel. In the same period, hospitalization associated with haematological toxicity was documented in 11% of the patients in the docetaxel cohort and in 15% of the patients in the cabazitaxel cohort. In the docetaxel cohort, 9.9% of patients required reverse isolation and 13% were diagnosed with sepsis during hospitalization. In the cabazitaxel cohort, the cumulative incidence was 7.9% and 15%, respectively. The median OS was reached at 21.9 months in the docetaxel cohort and, because of a later line of therapy, at 11.3 months in the cabazitaxel cohort. A multivariate Cox regression revealed that indicators of locally advanced and metastatic disease, severe comorbidities, and prior hormonal/cytotoxic therapies were independent predictors of early death.
Conclusion
Cabazitaxel patients face an increased risk of haematological toxicities during treatment. Together with their short survival time, this calls for a strict indication when using cabazitaxel in patients with mCRPC.
... Patient-specific multi-drug adaptive therapy requires the understanding of several factors: the frequency-dependent cycles of Fig. 3 | Examples of treatment implementation strategies for advanced prostate cancer. a | Default monotherapeutic sequencing in patients with metastatic castration-resistant prostate cancer (mCRPC): in addition to continuing androgen deprivation therapy (ADT), the current standard-of-care approach to treating mCRPC involves alternating between chemotherapy and anti-hormonal treatment [171][172][173]175,178 . b | Early introduction of therapy in high-risk localized prostate cancer: early intensive therapeutic interventions such as neoadjuvant hormonal therapy followed by radical prostatectomy or radiotherapy are currently being investigated in patients with high-risk localized prostate cancer [216][217][218] . ...
The introduction of second-generation androgen receptor antagonists (SG-ARAs) has greatly impacted the treatment of metastatic prostate cancer, providing tolerable and efficacious alternatives to chemotherapy. SG-ARAs provide similar therapeutic benefit to abiraterone, a potent CYP17 inhibitor, and do not require the co-administration of prednisone. Despite considerable improvements in clinical outcomes in the settings of both castration sensitivity and castration resistance, the durability of clinical response to the SG-ARAs enzalutamide, apalutamide and darolutamide, similar to abiraterone, is limited by inevitable acquired resistance. Genomic aberrations that confer resistance to SG-ARAs or provide potential alternative treatment modalities have been identified in numerous studies, including alterations of the androgen receptor, DNA repair, cell cycle, PI3K–AKT–mTOR and Wnt–β-catenin pathways. To combat resistance, researchers have explored approaches to optimizing the utility of available treatments, as well as the use of alternative agents with a variety of targets, including AR-V7, AKT, EZH2 and HIF1α. Ongoing research to establish predictive biomarkers for the treatment of tumours with resistance to SG-ARAs led to the approval of the PARP inhibitors olaparib and rucaparib in pre-treated metastatic castration-resistant prostate cancer. The results of ongoing studies will help to shape precision medicine in prostate cancer and further optimize treatment paradigms to maximize clinical outcomes.
... All compounds showed different degrees of selectivity to tumoral cells; however, 9c demonstrated high degree of cytotoxic selectivity to PC-3 cells, once it is considered that compounds with SI ratio higher than six as high selective compound (Lobo et al., 2015). It is known that androgens are critical for the development and maintenance of normal and cancer tissue and the AR is the main therapeutic target for advanced prostate cancer, nevertheless some types of prostate tumor grow in an androgen-independent manner and in those cases the treatment options are still limited (Kapoor et al., 2016). For this reason, we selected 9c and PC-3 to proceed the experiments. ...
Prostate cancer is among the most common cancer diagnoses in men, and the best treatment for patients with metastatic disease in advanced stages is still unclear. Previously, we have demonstrated that the three 1-(3-(aryl-4,5-dihydroisoxazol-5-yl)methyl)-4-trihalomethyl-1H-pyrimidin-2- ones derivatives (8a, 8e and 9c) present important cytotoxicity and selectivity for tumoral cells. Considering that various cytotoxic drugs have been assessed in patients with prostate cancer, but few drugs show survival advantage, we decided to study these three compounds (8a, 8e and 9c) in prostate cancer cells, androgen receptor (AR)-positive 22Rv-1 and AR-negative PC-3 cells. We obtained the half maximal inhibitory concentration (IC50) of 8a, 8e and 9c in prostate cancer cells and based on high selectivity of 9c to PC-3 cells, we determined the mechanism of this compound to induce cell death through different methods. We show here that 9c compound induces cell cycle arrest in G2/M, increasing the levels of reactive oxygen species and DNA damage, and triggers DNA damage response by ataxia-telangiectasia mutated (ATM) and histone H2AX phosphorylation induction. The compound also led PC-3 to lipid peroxidation and mitochondrial depolarization which triggered the activation of intrinsic pathway, confirmed by increase of cleaved caspase-9 and 3. In this work we also show the ability of 9c in reducing vascular endothelial growth factor expression (VEGF) and inhibiting topoisomerase I enzyme, therefore indicating a potential new molecule to be further investigated for prostate cancer management.
... To achieve the aims of palliative treatment, proper sequencing and effective combination of available agents becomes increasingly important for both clinicians and researchers. Although general guidelines on treatment options and algorithms exist [11,23,24], studies on the optimal choice, combination, and sequence of agents to maximize the clinical benefits (and minimize cross-resistance) [5,42] or define thresholds for therapy changes are lacking. ...
Purpose:
Treatments for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded rapidly. They include the chemotherapies docetaxel and cabazitaxel, hormonal drugs abiraterone and enzalutamide, and best supportive care (BSC). Cabazitaxel has proven to be the last life-prolonging option, associated with a significant risk of serious adverse events. Given the lack of real-world evidence, we aimed to compare healthcare resource utilization (HRU) and costs in patients with mCRPC treated with cabazitaxel, docetaxel, abiraterone, enzalutamide, and BSC.
Methods:
We used 2014-2017 claims data from a large German statutory health insurance fund, the Techniker Krankenkasse, to identify patients with mCRPC. Patient allocation to individual therapy regimens was based on clinical knowledge and included therapy cycles, duration of therapy, and continuous treatment. The study period lasted from the first claim until death, the end of data availability, a drug switch, or discontinuation of therapy, whichever came first. Multivariate regression models were used to compare monthly all-cause and mCRPC-related HRU and costs across cohorts by adjusting for baseline covariates (including age and comorbidities).
Results:
The 3944 identified patients with mCRPC initiated treatment with cabazitaxel (n = 240), docetaxel (n = 539), abiraterone (n = 486), enzalutamide (n = 351), or BSC (n = 2328). In most domains, HRU was highest in the cabazitaxel cohort and lowest in the BSC group. Accordingly, the highest all-cause and mCRPC-related costs per month, respectively, were observed in patients receiving cabazitaxel (€7631/€6343), followed by abiraterone (€5226/€4579), enzalutamide (€5079/€4416), docetaxel (€2392/€1580), and BSC (€959/€438). Cost variations were mostly attributable to drugs, inpatient treatment, and sick leave payments.
Conclusion:
mCRPC treatment imposes a high economic burden on statutory health insurance. Cabazitaxel is associated with substantially higher expenses, resulting from higher drug costs and a greater need for inpatient treatment. As mCRPC continues to be incurable, decision makers and clinician leaders should carefully evaluate public access to innovative agents and optimal treatment strategies.
... Docetaxel was the standard of care to treat mCRPC until the introduction of two androgen pathway-targeted treatments, enzalutamide (a second-generation androgen receptor inhibitor) and abiraterone acetate (an irreversible CYP17A1 inhibitor) combined with prednisone (abiraterone). These two agents received US Food and Drug Administration approval for use in mCRPC after docetaxel in August 2012 and April 2011, respectively, and then in chemotherapy-naïve mCRPC in September 2014 and December 2012, respectively [9]. Enzalutamide and abiraterone have delayed deterioration of health-related quality of life and increased survival for patients with chemotherapy-naïve mCRPC in clinical trial settings [10,11]. ...
Introduction:
Prostate cancer (PC) is the second leading cause of cancer death among US men and accounts for considerable healthcare expenditures. We evaluated economic outcomes in men with chemotherapy-naïve metastatic castration-resistant PC (mCRPC) treated with enzalutamide or abiraterone acetate plus prednisone (abiraterone).
Methods:
We performed a retrospective analysis on 3174 men (18 years or older) utilizing the Veterans Health Administration (VHA) database from 1 April 2014 to 31 March 2018. Men with mCRPC were included if they had at least one pharmacy claim for enzalutamide or abiraterone (first claim date = index date) following surgical or medical castration, had no chemotherapy treatment within 12 months prior to the index date, and had continuous VHA enrollment for at least 12 months pre- and post-index date. Men were followed until death, disenrollment, or end of study and were 1:1 propensity score matched (PSM). All-cause and PC-related resource use and costs per patient per month (PPPM) in the 12 months post index were compared between matched cohorts.
Results:
We identified 1229 men with mCRPC prescribed enzalutamide and 1945 prescribed abiraterone with mean ages of 74 and 73 years, respectively. After PSM, each cohort had 1160 patients. The enzalutamide cohort had fewer all-cause (2.51 vs 2.86; p < 0.0001) and PC-related outpatient visits (0.86 vs 1.03; p < 0.0001), with corresponding lower all-cause ($2588 vs $3115; p < 0.0001) and PC-related ($1356 vs $1775; p < 0.0001) PPPM outpatient costs compared with the abiraterone cohort. All-cause total costs (medical and pharmacy) PPPM ($8085 vs $9092; p = 0.0002) and PC-related total costs PPPM ($6321 vs $7280; p < 0.0001) were significantly lower in the enzalutamide cohort compared with the abiraterone cohort.
Conclusions:
Enzalutamide-treated men with chemotherapy-naïve mCRPC had significantly lower resource utilization and healthcare costs compared with abiraterone-treated men.
