Background Androgen receptor pathway inhibitors (ARPIs) improve the survival of men with various states of advanced prostate cancer, but complications, including bone fractures, have been associated with treatment. Although rates of SREs are reported in ARPI registration trials, real-world data describing SRE rates during treatment with ARPIs is lacking. Methods We conducted a global pharmacovigilance study using VigiBase, the World Health Organization’s international database of adverse drug reaction reports. All reports involving abiraterone, enzalutamide, apalutamide, or darolutamide in adult men from 2011 to September 2024 were included. Fractures were defined using standardized MedDRA terms, and disproportionality analyses quantified reporting odds ratios (RORs) with 95% confidence intervals and Bayesian shrinkage estimates (EB05). Two prespecified sensitivity analyses were performed, redefining the reference group as men on androgen deprivation therapy (ADT) alone and stratifying results by age groups. Results Among 282,143 VigiBase reports involving ARPIs, 1,140 (0.4%) included fractures. In primary analysis, ARPI therapy demonstrated a pharmacovigilance signal for increased SRE reporting (ROR 1.87, 95% CI 1.77–1.98; EB05 1.77). Signals were consistent for abiraterone, enzalutamide, and apalutamide, but not for darolutamide. Using ADT as reference, ARPIs remained associated with higher reporting of fractures (ROR 1.43, 95% CI 1.29–1.58; EB05 1.08). Age-stratified analyses demonstrated signals across all categories, with numerically larger disproportionality estimates among older men. Conclusions In this global pharmacovigilance analysis, ARPIs were consistently associated with increased reporting of fractures, including when compared with ADT alone. This highlights the potentially additive skeletal toxicity of treatment intensification, and underscore the importance of bone health monitoring and preventive strategies, particularly among older patients.

Introduction Masofaniten (EPI-7386) is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription, even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants, as a strategy to inhibit prostate cancer growth. In the Phase 1a dose-escalation study (NCT04421222), treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily pretreated mCRPC. We report here the results of the Phase 1b dose expansion first-in-human trial of EPI-7386 in mCRPC. Methods This Phase 1b, open-label, multicenter, dose expansion trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogens. Two cohorts were tested, examining the 600 mg BID and 600 mg QD dosing regimens. Circulating Tumor DNA (ctDNA) samples were also collected in the study at baseline and at cycle 4 to characterize the tumor genomic profile and quantify molecular response. Results 12 pts were enrolled in the 600 mg BID cohort (median follow up 12 months) and 12 in the 600 mg QD cohort (median follow up 8 months). Pts in both arms had a median of 2 (range 1-3) lines of prior therapy for mCRPC: 71% in both cohorts received abiraterone and at least one second generation AR inhibitor (enzalutamide, darolutamide or apalutamide). EPI-7386 was safe and well tolerated at both dosing schedules. The majority of related adverse events (AEs) were grade 1 (47%), and grade 2 (41%). AEs were consistent with AEs associated with second-generation antiandrogens (i.e. anemia, fatigue and hypertension), and no differences were observed between EPI-7386 600 mg QD and BID dosing. As expected, 600 mg BID dosing resulted in higher PK parameters at steady state, with a mean AUC0-24 of 357,000 hr*ng/mL and a mean Clast of 14,500 ng/mL, in comparison to a mean AUC0-24 of 246,000 hr*ng/mL and a mean Clast of 7,120 ng/mL for the 600 mg QD cohort. Both dosing regimens resulted in exposures in the range of those associated with antitumor activity in preclinical models. Evidence of antitumor activity was observed in ∼1/3 of the patients in both cohorts. Notably, genomic characterization of ctDNA samples showed, beside the expected alterations in the AR pathway (AR mutations, amplifications, structural rearrangements), additional molecular alterations associated with disease aggression and lineage plasticity (P53 mut, PTEN deletion, RB1 deletion). Conclusions Data from the Phase 1 dose expansion portion of the first-in-human study with EPI-7386 monotherapy confirmed the favorable safety and tolerability profile of the drug together with the achievement of clinically relevant exposures by both doses/regimens tested. Clinically relevant anti-tumor activity was observed in both arms in a small subset of patients displaying fewer molecular alterations outside of the AR pathway. Based on these observations, the clinical development of masofaniten is now focusing on its combination with other AR pathway inhibitors (NCT05075577; NCT05295927; NCT06312670) in earlier lines of treatment for mCRPC in combination with standard of care AR inhibitors.

BACKGROUND:Abemaciclib, a potent CDK4 and CDK6 inhibitor, has shown antitumour activity in prostate cancer models and in patients with metastatic castration-resistant prostate cancer (mCRPC) who have been heavily treated. We aimed to evaluate the safety and efficacy of abemaciclib in combination with abiraterone in patients with mCRPC. METHODS:CYCLONE 2 was a randomised, double-blind, placebo-controlled, phase 3 study done in 89 hospitals and academic and private research centres in 12 countries. All study parts had identical eligibility criteria, and used block randomisation with the same stratification factors (previous docetaxel treatment, presence of measurable disease, and type of progression). Participants were adults aged 18 years and older with histologically confirmed adenocarcinoma of the prostate and metastatic disease as documented by bone scans, CT scans, or MRI scans, and radiographic or PSA progression during continuous androgen deprivation therapy. Previous docetaxel for metastatic castration-sensitive prostate cancer was permitted; previous abiraterone, apalutamide, enzalutamide, darolutamide, or CDK4 and CDK6 inhibitors were exclusionary. The trial was conducted in three parts. Part 1 was a four-arm, placebo-controlled safety and dose-finding lead-in to determine the recommended phase 2 dose of abemaciclib with abiraterone. Participants were randomly assigned (2:2:1:1) to receive abiraterone (1000 mg orally once daily) and prednisone or prednisolone (5 mg orally twice daily) with either abemaciclib at 150 mg or 200 mg orally twice daily or with matching placebo (150 mg or 200 mg twice daily). In part 2 and part 3, patients were randomly assigned (1:1) to standard abiraterone and prednisone or prednisolone plus either abemaciclib at the recommended phase 2 dose or matching placebo. Patients, investigators, and sponsor were masked to treatment assignment. The primary outcome, investigator-assessed radiographic progression-free survival, was analysed in the intention-to-treat (participants from all study parts) population. Patients who received at least one dose of abiraterone, abemaciclib, or placebo were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03706365, and is completed. FINDINGS:Between Nov 26, 2018, and July 20, 2022, 515 patients were screened for eligibility, 393 of whom were randomly assigned, 206 patients to abemaciclib plus abiraterone and 187 to placebo plus abiraterone. The median age was 70·0 years (IQR 63·0-76·0). 289 (74%) of 393 patients identified as White, 80 (20%) as Asian, 17 (4%) as Black or African American, and seven (2%) as multiple race or not reported. The highest tested dose of 200 mg abemaciclib administered twice daily was chosen as the recommended phase 2 dose. The median follow-up time was 26·3 months (IQR 22·1-48·2) for the abemaciclib plus abiraterone group and 25·6 months (22·1-40·8) for the placebo plus abiraterone group. The primary endpoint of radiographic progression-free survival was not met: radiographic progression-free survival events were reported in 92 (45%) of 206 patients in the abemaciclib plus abiraterone group and 95 (51%) of 187 patients in the placebo plus abiraterone group (HR 0·83 [95% CI 0·62-1·11]; p=0·21). Median radiographic progression-free survival was 22·0 months (95% CI 19·3-27·5) for abemaciclib plus abiraterone and 20·3 months (16·5-24·4) for placebo plus abiraterone. The most common grade 3 or higher adverse events reported in the abemaciclib plus abiraterone group were anaemia (28 [14%] of 206 vs eight [4%] of 185 in the placebo plus abiraterone group), neutropenia (26 [13%] vs one [1%]), and alanine aminotransferase increase (18 [9%] vs 12 [6%]). Serious adverse events occurred in 91 (44%) of 206 patients in the abemaciclib plus abiraterone group and in 68 (37%) of 185 patients in the placebo plus abiraterone group. There were three treatment-related deaths due to interstitial lung disease in the abemaciclib plus abiraterone group. INTERPRETATION:Dual inhibition of CDK4 and CDK6 and the androgen receptor pathway with abemaciclib plus abiraterone did not improve radiographic progression-free survival compared with abiraterone alone in the CYCLONE 2 study population with mCRPC. Safety of the combination was consistent with the previously reported safety of the individual drugs. Additional research is required to identify effective combination therapies for patients with mCRPC, especially in those presenting with adverse prognostic characteristics. FUNDING:Eli Lilly.

BACKGROUND AND OBJECTIVE:Darolutamide + docetaxel + androgen-deprivation therapy (ADT) significantly improved overall survival (OS) and delayed time to disease progression versus docetaxel + ADT in ARASENS (NCT02799602). We report data on subsequent antineoplastic therapies received and associated OS after discontinuation of the study treatment. METHODS:Patients were randomized 1:1 to darolutamide 600 mg orally twice daily or placebo, both with docetaxel + ADT. After treatment discontinuation, patients entered follow-up periods during which information on subsequent therapies and survival was collected. Postprogression OS was estimated using the Kaplan-Meier method as the time from initiation of first subsequent therapy to death and was compared in multivariable Cox regression analyses. KEY FINDINGS AND LIMITATIONS:Of the 1305 patients treated, 315/651 who received darolutamide and 495/654 who received placebo entered follow-up, and 57% and 76% of these patients, respectively, received subsequent therapy. In the darolutamide group, first subsequent therapy was either an androgen receptor pathway inhibitor (ARPI; 63%) or a taxane (29%), and corresponding postprogression median OS was similar (13 vs 11 mo; hazard ratio [HR] 1.25, 95% confidence interval [CI] 0.50-3.09). In the placebo group, first subsequent therapy was an ARPI in 78% and a taxane in 19% of cases, with worse OS for the taxane versus ARPI subgroup (14 vs 23 mo; HR 3.18, 95% CI 1.56-6.50). The main limitation of these analyses is their post hoc nature. CONCLUSIONS AND CLINICAL IMPLICATIONS:For ARPI-naïve patients who did not receive darolutamide in ARASENS, postprogression survival was longer with subsequent ARPI versus taxane treatment, but OS remained shorter in comparison to the darolutamide group. Decisions on postprogression therapy should consider disease volume and drugs with different mechanisms of action.

BACKGROUND AND OBJECTIVE:We aimed to assess the comparative effectiveness of contemporary systemic treatment options across patients with metastatic hormone-sensitive prostate cancer (mHSPC) across clinically relevant prognostic subgroups (synchronous high [SHV] and low [SLV] volume, and metachronous high [MHV] and low [MLV] volume). METHODS:This living network meta-analysis was conducted using the living interactive evidence (LIvE) synthesis framework. Phase 3 randomized controlled trials assessing treatment intensification with androgen receptor pathway inhibitors (ARPIs), docetaxel (D), or both were included. Mixed treatment comparisons were conducted for overall population and for each prognostic subgroup (SHV, SLV, MHV, and MLV). Overall survival (OS) and progression-free survival were assessed. KEY FINDINGS AND LIMITATIONS:The current report of a living systematic review includes a total of 11 trials (12 668 patients and 12 unique treatments). In the overall population, the results were consistent with those of a previous report. An analysis of OS by prespecified subgroups included nine clinical trials (8990 patients and eight unique treatments). In the SHV subgroup (N = 5171; 57%), ARPI + D + androgen deprivation therapy (ADT) led to a statistically significant improvement in OS compared with D + ADT (hazard ratio: 0.72; 95% confidence interval: 0.62-0.83) and ARPI + ADT (0.71; 0.53-0.97). In the SLV subgroup (N = 2455; 27%), ARPI + ADT led to a statistically significant improvement compared with ADT alone (0.65; 0.52-0.80). There was no statistically significant difference between ARPI + D + ADT and ARPI + ADT (1.08; 0.65-1.79). In the MHV subgroup (N = 589; 6.5%), no statistically significant improvement was observed with ARPI + D + ADT compared with ARPI + ADT (0.89; 0.43-1.85) and D + ADT (0.90; 0.60-1.36). There was no statistically significant difference between ARPI + ADT and D + ADT (1.02; 0.45-2.28). In the MLV subgroup (N = 775; 8.5%), ARPI + ADT led to a statistically significant improvement compared with ADT alone (0.43; 0.29-0.64) and D + ADT (0.41; 0.24-0.70). There was no statistically significant difference between ARPI + D + ADT and ARPI + ADT (1.56; 0.40-6.25). Inherent limitations of this analysis include the inability to account for all relevant variables such as the patient- and cancer-related factors that likely influenced the decision of physicians to offer docetaxel to patients. CONCLUSIONS AND CLINICAL IMPLICATIONS:Current evidence suggests that triplet systemic therapy is preferred for patients with SHV mHSPC who are fit for docetaxel. Androgen receptor pathway doublet therapy is preferred for all other patient subgroups compared with ADT alone. There is no role of docetaxel doublet in patients with access to ARPI therapy and if they are able to receive it.

Supplemental Methods, Table 1 and Figures 1-2. Appendix I: TGI PSA kinetic model, Appendix II: Survival analysis. Supplementary Table 1. Parameter estimates of the final PSA kinetic model. Supplementary Figure 1. Diagnostic plot of the observed and predicted PSA concentrations for the PSA kinetic models. Supplementary Figure 2. Comparison of predicted survival probability based on the final multivariate PSA-survival model to the observed survival probability over time.

BACKGROUND:Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. OBJECTIVE:To present the results from the APCCC 2019. DESIGN, SETTING, AND PARTICIPANTS:Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS:Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS:These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. PATIENT SUMMARY:The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.

Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

Background: In the global Phase-3 Selective Prostate Androgen Receptor Targeting with ARN-509 study, apalutamide plus ongoing androgen deprivation therapy (ADT) significantly increased metastasis-free survival (MFS) and improved other clinical outcomes in men with nonmetastatic castration-resistant prostate cancer (nm-CRPC) who were at high risk of developing metastases. In this subpopulation analysis of Selective Prostate Androgen Receptor Targeting with ARN-509 study, the efficacy and safety of apalutamide plus ADT were evaluated in Japanese patients with nm-CRPC. Methods: The primary efficacy end point was MFS. Secondary efficacy end points were time to metastasis, progression-free survival, symptomatic progression, initiation of cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic parameters were also assessed. Results: Fifty-five Japanese patients with ongoing ADT were randomized (apalutamide: n = 34, placebo: n = 21). Median treatment duration was 5.7 months in the apalutamide group and 11.0 months in the placebo group. Median MFS was not reached in the apalutamide group (95% confidence interval: 10.97, not estimable) and was 18.23 months (95% confidence interval: 11.04, 18.50) in the placebo group. Secondary end points were improved in the apalutamide group. The safety profile of apalutamide with ADT was comparable with the global population, and no new safety signals were identified in this Japanese subpopulation. Although, apalutamide exposure tended to be higher in the Japanese subpopulation compared with the non-Japanese population, this was likely to be explained by body weight and considered not clinically meaningful. Conclusion: In the Japanese subpopulation, treatment with apalutamide with ADT resulted in favorable efficacy outcomes with comparable benefit-risk profile to the global population with nm-CRPC who are at high-risk of developing metastases. (C) 2020 Asian Pacific Prostate Society. Published by Elsevier B.V.

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have rising prostate-specific antigen (PSA) and castrate testosterone levels, with no radiological findings of metastatic disease on computed tomography and bone scan. Given recent drug approvals for nmCRPC, with many other therapeutics and imaging modalities being developed, management of nmCRPC is a rapidly evolving field that merits detailed investigation.To review current nmCRPC management practices and identify opportunities for improving care of nmCRPC patients.A literature search up to July 2018 was conducted, including clinical trials and clinical practice guidelines (National Comprehensive Cancer Network, European Society for Medical Oncology, European Association of Urology, Prostate Cancer Clinical Trials Working Group, Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence). Keywords included prostate cancer, nonmetastatic, castration resistance, rising PSA, and biochemical relapse.Recommendations regarding indications for, and frequency of, imaging and PSA testing, as well as for initiating systemic therapy in nmCRPC are based on PSA rise kinetics and symptoms. Both enzalutamide and apalutamide have been shown to significantly increase metastasis-free survival in phase III placebo-controlled randomised trials in nmCRPC patients with PSA doubling time (DT) ≤10 mo. The expected impact of new imaging techniques in the assessment of nmCRPC is also reviewed.nmCRPC is a heterogeneous disease; while observation may be an option for some patients, enzalutamide and apalutamide may be appropriate to treat nmCRPC patients with PSA-DT ≤10 mo. The emergence of more accurate imaging modalities as well as circulating tumour biomarker assays will likely redefine the assessment of nmCRPC in the near future.Herein, we review key literature and clinical practice guidelines to summarise the optimal management of patients with prostate cancer and rising prostate-specific antigen despite castrate testosterone levels, but with no evidence of distant metastasis on traditional imaging. New drugs are being developed for this disease setting; novel imaging and tumour biomarker blood tests are likely to define this disease state more accurately.

PURPOSE: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.PATIENTS AND METHODS: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.RESULTS: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).CONCLUSION: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.