Androgen receptor-targeted therapies - avoid clinically relevant interactions

Statins and antiepileptic drugs (AEDs) are frequently coprescribed to individuals with hypercholesterolemia and new-onset seizures. Statins are metabolized by the cytochrome P450 (CYP) enzyme system. Interactions between statins and agents that undergo CYP metabolism are common. In this study, the effects of two commonly prescribed AEDs, lamotrigine and phenytoin, with different routes of metabolism (CYP3A4 versus glucuronic acid conjugation) on atorvastatin pharmacokinetics were evaluated. Healthy volunteers (n=119) received atorvastatin 40 mg/day for 7 days followed by addition of lamotrigine (target 300 mg/day) or phenytoin (target ~4 mg/kg per day) in this open-label, single-sequence, two-cohort study. Serial pharmacokinetic sampling of atorvastatin was conducted on day 7 of atorvastatin dosing and day 70 of lamotrigine + atorvastatin dosing or day 28 of phenytoin + atorvastatin dosing. Main outcome measures were steady-state area under the curve over the 24-h dosing interval (AUC((0-τ)) ) and maximum concentration (C(max) ) of atorvastatin and its metabolites, 2OH-atorvastatin and 4OH-atorvastatin, in the presence of lamotrigine or phenytoin. When atorvastatin was administered with lamotrigine compared with when atorvastatin was administered alone, atorvastatin AUC((0-τ)) was within bounds indicating no interaction, whereas C(max) was slightly higher(14%); AUC((0-τ)) and C(max) were 3% and 20% higher, respectively, for 2OH-atorvastatin and 25% and 21% higher, respectively, for 4OH-atorvastatin.When atorvastatin was administered with phenytoin compared with when atorvastatin was administered alone, reductions in AUC((0-τ)) and C(max) were observed for atorvastatin (54% and 24%, respectively), 2OH-atorvastatin (53% and 22%, respectively), and 4OH-atorvastatin (44% and 52%, respectively). Pharmacokinetics of atorvastatin were not significantly affected by coadministration with lamotrigine. Phenytoin significantly reduced atorvastatin bioavailability. Consistent with the published literature, these data are consonant with the possibility that atorvastatin does not require dose adjustment when coadministered with lamotrigine at doses to 300 mg/day, whereas atorvastatin coadministered with phenytoin may require atorvastatin dose adjustment to maintain atorvastatin exposure.

All the currently available protease inhibitors are metabolised by the cytochrome P450 (CYP) enzyme system. All are inhibitors of CYP3A4, ranging from weak inhibition for saquinavir to very potent inhibition for ritonavir. Thus, they are predicted to have numerous drug interactions, although few such interactions have actually been documented either in pharmacokinetic studies or in clinical reports. This article reviews the published literature with an emphasis on the magnitude of interactions and on practical recommendations for management. Many of the drugs commonly taken by patients with HIV have a strong potential to interact with the protease inhibitors. In particular, the non-nucleoside reverse transcriptase inhibitors are also metabolised by CYPand have been shown to interact with protease inhibitors. Delaviridine is an inhibitor of CYP3A4, but nevirapine and efavirenz are inducers of CYP3A4. The protease inhibitors also interact with each other, and these interactions are being explored for their potential therapeutic benefits. Other commonly used drugs are also known to affect protease inhibitor metabolism, including inhibitors such as clarithromycin and the azole antifungals and inducers such as the rifamycins. Drugs that are known to be significantly affected by the protease inhibitors include ethinylestradiol and terfenadine; many other drugs have lesser or potential interactions. Although little specific data is available on the drug interactions of protease inhibitors, this lack of data should not be interpreted as a lack of interaction. Retrospective chart reviews have demonstrated that potentially severe drug interactions are frequently overlooked. Much more clinical data is needed, but pharmacists and physicians must always be vigilant for drug interactions, both those that are already documented and those that are predictable from pharmacokinetic profiles, in patients receiving protease inhibitors.

Department of Anesthesia, Stanford University School of Medicine, Stanford, California, and Veterans Affairs Palo Alto Healthcare System, Palo Alto, California. djclark@stanford.eduMETHADONE has become one of the darling drugs of the pain management community and is used in a variety of situations. Far from being restricted to use in addiction treatment centers, the drug is now frequently prescribed for the management of pain related to malignancies and even more frequently for nonmalignant types of pain. One review found the number of population-adjusted methadone prescriptions increased 727% from 1997 to 2004, and that this increase was due in general to an increase in prescriptions for pain.1The readers of this journal may also be familiar with the drug’s use perioperatively when a sustained base of analgesia is desired as part of the anesthetic plan or perioperative pain management scheme. Indeed, this drug has many properties making it useful in these settings. It is potent and has high efficacy, excellent absorption from the gastrointestinal tract, no known active metabolites, very low cost, and both oral and intravenous formulations. The weak noncompetitive N -methyl-d-aspartate receptor antagonism possessed by methadone may further enhance the analgesia of the drug. The name of one of the first formulations, Dolophine, in fact, comes from dolor (“pain”) and fin (“end”). What could possibly be the problem with this pain-ending drug? As explained by Totah et al. in the introduction to their article, “Role of CYP2B6 in Stereoselective Human Methadone Metabolism,” the drug has an exceedingly variable but generally slow hepatic clearance.2The variable but usually very long half-life governed by this slow clearance has raised serious concerns over this drug’s safety.The chief serious hazard associated with this opioid when used for pain management is respiratory depression. What makes this particular opioid more problematic than most is that accumulation to steady state can take a week or more. This slow approach to steady state levels brings with it the possibility that side effects can also appear slowly. In the majority of cases, the drug is administered to outpatients; therefore, the patients are unmonitored as the drug accumulates. Specific populations such as the elderly or those prone to abuse of medications may be at particular risk for delayed respiratory depression caused by methadone. Data strongly support the notion that methadone’s slow accumulation can have lethal consequences. For example, Sims et al. 1found that the number of methadone deaths increased 1,770% from 1997 to 2003. Appalachian states once hard hit by OxyContin abuse now seem to be particularly hard hit by methadone-related problems as well.3Many other articles have commented on methadone’s particular problem with slow accumulation and toxicity and have generally recommended a “start low, go slow” approach.4,5It is quite rational, then, to focus studies on methadone’s metabolism to predict who might be particularly prone to methadone-related toxicity, and under what circumstances toxicity might be seen.Investigators have for some time been interested in methadone’s hepatic clearance. The cytochrome P450 (CYP) enzyme system has long been known to play a major role in first phase methadone metabolism. The more important unanswered question has been, “Which isoform?” The hepatic CYP enzyme family has approximately 50 members expressed in humans. Many are concentrated in the liver, although CYP-mediated metabolism occurs in many other organs, including the gut, lungs, and brain. Far from drug specific, individual drugs can be substrates for multiple CYPs. Making matters more complex, the predominant metabolizing isoform may depend on which isomer of a racemic mixture of drug is being followed. With respect to methadone metabolism, several isoforms including the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 have been implicated. This might prompt the reader to ask what the value of further study would be if there are so many enzymes known to be involved. The goal of the studies of Totah et al. was therefore not necessarily to ask which enzymes are able under some set of conditions to metabolize the drug, but to assess which isoforms really do dominate human metabolism, thus providing us a more clinically useful metabolic characterization. The answer in this case was not entirely expected. Using a series of pharmacologic tools and a rigorous analytical strategy, the authors were able to implicate the CYP2B6 enzyme as that responsible for the bulk of methadone metabolism in humans, particularly the S -methadone isomer. Therefore, not only overall plasma levels but also the ratio of plasma methadone isomers is controlled by CYP2B6.2Of special note are genetic factors impacting metabolism through the CYP enzyme system, particularly the CYP2B6 and CYP3A4 isoforms the authors conclude are likely important for hepatic methadone metabolism. Both genes are polymorphic in humans, and the polymorphic nature of both genes has been demonstrated to affect the rates or clearance, production of metabolites, and probability of reaching clinical endpoints for various drugs, including methadone. Crettol et al. ,6for example, attempted to associate CYP2B6, CYP2C9, and CYP2C19 polymorphisms with methadone plasma levels in 209 patients in methadone maintenance with positive associations found for only the CYP2B6 variants. The predominant effects were on S -methadone levels, which is consistent with the findings of Totah et al. 2In a follow-up study by the same group involving 245 patients in methadone maintenance, these authors reproduced their initial genetic associations with S -methadone metabolism and CYP2B6 variants, although CYP3A4 activity was also linked to plasma methadone levels in this study.7Zanger et al. 8have demonstrated the CYP2B6 enzyme to be highly polymorphic, and more detailed studies will be required to determine which haplotypes of the more than 100 single nucleotide polymorphisms are associated with altered enzymatic activity. Other studies have associated CYP3A4 activity with total methadone plasma concentrations, and possibly with the rare methadone-related complication of prolonged QT interval and torsade de pointes.9The genetics and impact on disease have been far more carefully studied for CYP3A4, and many publications are dedicated to variants of the gene for this enzyme as they impact drug disposition of opioids, benzodiazepines, chemotherapeutics, and other drugs as well as susceptibility to diseases, particularly cancers.The field of medicine is experiencing growing interest toward individualizing medical care. This approach to therapy takes into account multiple aspects of a patient’s makeup when selecting and implementing treatments. Determinants of drug metabolism figure prominently in this approach. Methadone is an effective treatment option for many patients but has a clear record of at least one severe complication, respiratory arrest. Better understanding the process of clearance of this drug stands a reasonable chance of improving the safety and outcomes of methadone use in patients, particularly if genetic or other types of profiling could be shown to accurately predict plasma drug levels. Understanding the control of individual isomer levels for racemic drugs in which the isomers have different pharmacologic properties needs to be taken into account. With their expertise in the investigation of drug disposition, laboratories like those of Totah et al. 2are in excellent position to help anesthesiology and its related fields take a lead position in this emerging area of medicine.Department of Anesthesia, Stanford University School of Medicine, Stanford, California, and Veterans Affairs Palo Alto Healthcare System, Palo Alto, California. djclark@stanford.edu

e22141 Background: Prostate cancer (PRCA) is driven by the Androgen Receptor (AR), a cytoplasmic protein that translocates to the nucleus to activate a transcriptional program critical to PRCA tumorigenesis. The AR is the major therapeutic target in PRCA, with multiple drugs that improve survival and quality of life for men with advanced PRCA. However, few biomarkers can assay for AR activity to identify those most likely to benefit from AR-targeting therapies. Methods: Utilizing a novel microfluidic technology known as the VERSA (Vertical Exclusion-based Rare Sample Analysis) platform, CTCs were captured and purified from men with advanced PRCA who had failed androgen deprivation therapy. CTCs were then stained and imaged via epiflourescent microscopy for EpCAM, AR, Hoechst and CD45. The enhanced optical imaging of the VERSA platform enabled subcellular localization of the AR and calculation of the relative amount of AR localized to the nucleus as a biomarker of resistance to AR-targeting therapies. Results: CTCs were prospectively collected and analyzed for AR nuclear localization. Significant heterogeneity in AR localization was found between patients who had failed androgen deprivation therapy with the mean nuclear AR ranging from 20-57% of total AR. Significant intra-patient heterogeneity was also identified with the percentage of AR localized to the nucleus ranging from 11-77% of total AR. DNA and mRNA have been isolated from these cells to analyze for underlying mechanisms of nuclear localization. Conclusions: The VERSA platform is able to analyze subcellular localization of proteins in CTCs followed by total nucleic acid extraction. We show that among men whose disease has progressed through androgen deprivation, a significant portion of the AR is localized to the nucleus as a possible biomarker of resistance to AR targeting therapies. We also identify significant heterogeneity in AR localization among CTCs, suggesting resistant PRCA clones that have greater proliferative potential.

Second-line treatment options in metastatic castration-resistant prostate cancer after progression on first-line androgen-receptor targeting therapies: A systematic review and Bayesian network analysis

It is well recognized that herbal supplements or herbal medicines are now commonly used. As many patients taking prescription medications are concomitantly using herbal supplements, there is considerable risk for adverse herbal drug interactions. Such interactions can enhance the risk for an individual patient, especially with regard to drugs with a narrow therapeutic index such as warfarin, cyclosporine A and digoxin. Herbal drug interactions can alter pharmacokinetic or/and pharmacodynamic properties of administered drugs. The most common pharmacokinetic interactions usually involve either the inhibition or induction of the metabolism of drugs catalyzed by the important enzymes, cytochrome P450 (CYP). The aim of the present article is to provide an updated review of clinically relevant metabolic CYP-mediated drug interactions between selected herbal supplements and prescription drugs. The commonly used herbal supplements selected include Echinacea, Ginkgo biloba, garlic, St. John's wort, goldenseal, and milk thistle. To date, several significant herbal drug interactions have their origins in the alteration of CYP enzyme activity by various phytochemicals. Numerous herbal drug interactions have been reported. Although the significance of many interactions is uncertain but several interactions, especially those with St. John's wort, may have critical clinical consequences. St. John's wort is a source of hyperforin, an active ingredient that has a strong affinity for the pregnane xenobiotic receptor (PXR). As a PXR ligand, hyperforin promotes expression of CYP3A4 enzymes in the small intestine and liver. This in turn causes induction of CYP3A4 and can reduce the oral bioavailability of many drugs making them less effective. The available evidence indicates that, at commonly recommended doses, other selected herbs including Echinacea, Ginkgo biloba, garlic, goldenseal and milk thistle do not act as potent or moderate inhibitors or inducers of CYP enzymes. A good knowledge of the mechanisms of herbal drug interactions is necessary for assessing and minimizing clinical risks. These processes help prediction of interactions between herbal supplements and prescription drugs. Healthcare professionals should remain vigilant for potential interactions between herbal supplements/medicines and prescription drugs, especially for drugs with a narrow therapeutic index are used.

Phosphodiesterase-5 inhibitors (PDE5i, sildenafil, vardenafil, tadalafil and avanafil) are a first-line medical therapy for erectile dysfunction (ED). In all likelihood, PDE5i usage will increase because sildenafil (Viagra® and Revatio®) and tadalafil (Cialis® and Adcirca ®) have recently been recommended as first-line therapy for patients with pulmonary hypertension (PH). PDE5i exhibit higher plasma concentrations when co-administered with cytochrome P (CYP) 3A inhibitors, which influences their side-effect profile. The higher PDE5i plasma concentrations, caused by CYP3A inhibitors, influence the severity and timing of PDE5i drug interactions and require dose adjustment. PDE5i are safe when used with most antihypertensive agents, but co-administration with nitrates or α-blockers can cause severe hypotension and syncope. Dose adjustment is also necessary when PDE5i are co-administered with CYP3A inducers. The combination of oral tadalafil and bosentan (endothelin receptor antagonist) reduces tadalafil levels and requires dose adjustment. Current literature reports a number of interactions between PDE5i and other agents and further studies are needed to expand our knowledge base of these interactions. This review discusses relevant PDE5i drug interactions, including those with CYP 450 inhibitors and inducers which are frequently used during the treatment of ED and PH.

Reprogrammed lipid metabolism with massive upregulation of tumor cell-autonomous synthesis of saturated fatty acids is a hallmark of prostate cancer (PCa) and is driven in part by aberrations in androgen receptor (AR) signaling. While lipid alterations are well described in primary PCa, the extent to which the circulating lipidome reflects tumor-associated metabolic changes in metastatic disease, and its role in therapy response, remains to be determined. This study aims to assess whether plasma lipid profiling captures tumor metabolic rewiring, and whether this reflects response to AR-targeting therapy, in metastatic castration-resistant PCa (mCRPC). Quantitative plasma lipidomics was performed on plasma samples collected from patients with mCRPC (n = 50) and cancer-free subjects (C-FS, n = 14). Samples from patients with mCRPC were collected longitudinally at the time of progression on androgen deprivation therapy prior to initiation of first-line enzalutamide (Enza), after the start of treatment with Enza, before progression on Enza. Compared to C-FS, patients with mCRPC showed distinct lipidomic signatures, characterized by increased levels of monounsaturated lipids and altered composition of the phospholipid and sphingolipid pool, mimicking the aberrations known to occur in primary PCa tissue. Enza treatment markedly reduced total lipid levels, decreased major phospholipid classes and ceramides, while increasing sphingomyelins. Notably, quantitative differences in specific sphingolipid species occurring after Enza treatment correlated with survival outcomes. Plasma lipidomics reflects key metabolic features of PCa and is profoundly impacted by AR inhibition, with prognostic relevance in patients with mCRPC. These findings support its potential as a non-invasive tool for monitoring disease activity and treatment response, and lay the groundwork for lipid-based biomarkers in mCRPC, while indicating that the lipidomic alterations observed may help inform ongoing and forthcoming research on metabolic targeting.

Evidence for a new human CYP1A1 regulation pathway involving PPAR-α and 2 PPRE sites

Despite the global prevalence of herbal medicine use and the common perception of their safety, substantial evidence indicates a significant potential for clinically relevant herb-drug interactions that may affect the pharmacokinetics and pharmacodynamics of co-administered pharmaceuticals. This critical issue poses a considerable threat to patient safety and the effectiveness of conventional treatments, primarily through modulation of the cytochrome P450 (CYP450) enzyme system, a key metabolic pathway for many drugs. This research aims to elucidate how herbal remedies affect CYP450 enzyme activity, thereby influencing drug pharmacokinetics. Our methodology involves a comprehensive critical evaluation of existing scientific data from in silico, in vitro, and in vivo studies, clinical trials, and meta-analyses to identify specific herbal medicines with significant effects on CYP450. The investigation outlines their mechanisms of action, distinguishing between enzyme induction, which can diminish drug efficacy, and inhibition, which may lead to increased drug concentrations and toxicity. It was highlighted that certain medicinal plants and their bioactive compounds may act as inducers or inhibitors across major isoforms, including CYP1A2, CYP2C9, CYP2D6, and CYP3A4. Comprehensive data were compiled for ten plant species with the most extensive scientific information regarding their effects on CYP450, namely St John's wort (Hypericum perforatum L.), Echinacea (Echinacea purpurea (L.) Moench), Ginkgo (Ginkgo biloba L.), Danshen (Salvia miltiorrhiza Bunge), Garlic (Allium sativum L.), Ginger (Zingiber officinale Roscoe), Milk thistle (Silybum marianum L. Gaertn.), Black cohosh (Actaea racemosa L.), Ginseng (Panax ginseng C.A. Mey), and Liquorice (Glycyrrhiza glabra L.). Ultimately, this study underscores the vital role of the CYP450 system in mediating these interactions and advocates for increased awareness among healthcare professionals and patients. Looking ahead, conducting robust, standardised clinical trials, developing predictive interaction models, and performing comprehensive analyses of herbal constituents are crucial to ensuring safe and effective pharmacotherapy involving herbal medicines.

Interindividual variability in xenobiotic metabolism and drug response is extensive and genetic factors play an important role in this variation. A majority of clinically used drugs are substrates for the cytochrome P450 (CYP) enzyme system and interindividual variability in expression and function of these enzymes is a major factor for explaining individual susceptibility for adverse drug reactions and drug response. Because of the existence of many polymorphic CYP genes, for many of which the number of allelic variants is continually increasing, a universal and official nomenclature system is important. Since 1999, all functionally relevant polymorphic CYP alleles are named and published on the Human Cytochrome P450 Allele (CYP-allele) Nomenclature Web site (http://www.cypalleles.ki.se). Currently, the database covers nomenclature of more than 660 alleles in a total of 30 genes that includes 29 CYPs as well as the cytochrome P450 oxidoreductase (POR) gene. On the CYP-allele Web site, each gene has its own Webpage, which lists the alleles with their nucleotide changes, their functional consequences, and links to publications identifying or characterizing the alleles. CYP2D6, CYP2C9, CYP2C19, and CYP3A4 are the most important CYPs in terms of drug metabolism, which is also reflected in their corresponding highest number of Webpage hits at the CYP-allele Web site.The main advantage of the CYP-allele database is that it offers a rapid online publication of CYP-alleles and their effects and provides an overview of peer-reviewed data to the scientific community. Here, we provide an update of the CYP-allele database and the associated nomenclature.

On Warfarin Use in Kidney Disease: A Therapeutic Window of Opportunity?

BackgroundInsulin resistance (IR) in hepatocytes endangers human health, and frequently results in the development of non-alcoholic fatty liver disease (NAFLD). Research on m6A methylation of RNA molecules has gained popularity in recent years; however, the molecular mechanisms regulating the processes of m6A modification and IR are not known. The cytochrome P450 (CYP450) enzyme system, which is mainly found in the liver, is associated with the pathogenesis of NAFLD. However, few studies have been conducted on CYP450 related m6A methylation. Here, we investigated the role of the methyltransferase METTL3 in exacerbating IR in hepatocytes, mainly focusing on the regulation of m6A modifications in CYP2B6.Methods and resultsAnalysis using dot blot and epitranscriptomic chips revealed that the m6A modification pattern of the transcriptome in high-fat diet (HFD)-induced fatty liver and free fatty acid (FFA)-induced fatty hepatocytes showed significant changes. CYP450 family members, especially Cyp2b10, whose homolog in humans is CYP2B6, led to a noticeable increase in m6A levels in HFD-induced mice livers. Application of the METTL3 methyltransferase inhibitor, STM2457, increased the level of insulin sensitivity in hepatocytes. We then analyzed the role of METTL3 in regulating m6A modification of CYP2B6 in hepatocytes. METTL3 regulated the m6A modification of CYP2B6, and a positive correlation was found between the levels of CYP2B6 translation and m6A modifications. Furthermore, interference with METTL3 expression and exposure to STM2457 inhibited METTL3 activity, which in turn interfered with the phosphorylated insulin receptor substrate (pIRS)-glucose transporter 2 (GLUT2) insulin signaling pathway; overexpression of CYP2B6 hindered IRS phosphorylation and translocation of GLUT2 to membranes, which ultimately exacerbated IR.ConclusionThese findings offer unique insights into the role that METTL3-mediated m6A modifications of CYP2B6 play in regulating insulin sensitivity in hepatocytes and provide key information for the development of strategies to induce m6A modifications for the clinical treatment of NAFLD.

The investigation of the mechanism(s) of benzene toxicity/leukemogenesis over the past 50 years has been contemporaneous with developments in the study of xenobiotic metabolism. Research on the cytochrome P450 (CYP) enzyme system, and related systems in vivo and in vitro, which culminated in the isolation and reconstitution of the many CYPs, established pathways for the study of xenobiotic metabolism and its relationship to the biological activity of many chemicals. The essential role for metabolism of benzene as a precursor to the demonstration of benzene toxicity led to extensive studies of benzene metabolism, many of which will be reviewed here. Benzene toxicity/leukemogenesis, however, is a function of the bone marrow, a site remote from the liver where most benzene metabolism occurs. Studies of benzene metabolism have delineated the array of metabolites which appear to play a role in bone marrow damage, but further studies, both in vivo and in vitro, using appropriate animal models, will be needed to fully understand the impact of benzene and its metabolites on bone marrow function.

TPS5104 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has been shown to prolong survival, delay disease progression, and improve quality of life, raising hopes that these gains will be amplified with even more cancer-specific targets and more powerful radioligands. Human kallikrein-related peptidase 2 (hK2) is a tumor-associated member of the kallikrein family that shares significant homology to prostate-specific antigen and is minimally expressed in normal non-prostate tissues. JNJ-69086420 (JNJ-420; 225Ac-DOTA-h11B6 [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid]), is a first-in-class radioimmunotherapy targeted to hK2 antigen. In a phase 0 study of [111In]-DOTA-h11B6, patients with mCRPC (progressed on standard therapies), treatment with a single dose of [111In]-DOTA-h11B6 (2 mg) with/without 8 mg h11B6, demonstrated safety, good tumor localization, nominal normal-organ uptake, and no difference in pharmacokinetics (PK) between 2 and 10 mg antibody mass (Morris et al. J Clin Oncol. 2021 39:6 suppl, 122). We have initiated the first-in-human study to assess the safety, PK, pharmacodynamic (PD), and clinical activity of Ac-225 radiolabeled JNJ-420, to determine its recommended phase 2 dose (RP2D) in adults with advanced PC. Methods: This open-label, multicenter, phase 1 study will recruit approximately 50 men (aged ≥18 years) with advanced PC across dose escalation (Part 1) and expansion (Part 2) parts. Key eligibility criteria: mCRPC with histologic confirmation of adenocarcinoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function based on hematology and serum chemistry, and 1 or more prior novel androgen receptor-targeted therapies (prior chemotherapy acceptable). Key exclusion criteria: prior treatment with radium/strontium/samarium/radioconjugate therapy, superscan findings as protocol defined, active central nervous system metastases. In Part 1, men will receive intravenous (IV) injection of 50 μCi/ 2 mg JNJ-420 (once every 8 weeks) with one or multiple doses; escalation of dose levels to be based on dose limiting toxicities (DLTs) evaluation, until RP2D identification. In Part 2, JNJ-420 is to be given at one of the RP2D(s) determined in Part 1. Primary endpoint is safety (incidence and severity [grading per NCI-CTCAE V5.0] of AEs including DLTs). Secondary endpoints include prostate specific antigen response rate, overall response rate (PCWG3 modified RECIST 1.1 criteria), PK, PD, immunogenicity, and biomarker analyses. Enrollment began in Dec 2020; as of 10 Feb 2022, 4 sites have been initiated and 23 patients enrolled; currently, dose escalation is ongoing. Clinical trial information: NCT04644770.