Price transparency & out-of-pocket payments for medications: Implications of associated delivery fees in the United States.

The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved substantially over the past decade, with androgen receptor pathway inhibitors, taxanes, poly (ADP-ribose) polymerase (PARP) inhibitors, radioisotopes, bone-protecting agents, and emerging targeted therapies improving survival for patients. At the same time, earlier treatment intensification in the hormone-sensitive setting has resulted in heterogeneous clinical presentations at the onset of castration resistance, adding complexity to treatment sequencing and clinical decision making. Here, we propose a pragmatic, patient-centered framework to help guide the management of mCRPC by integrating clinical features, molecular profiling, imaging findings, and supportive care considerations. Confirmation of castration resistance remains a critical first step and requires documented biochemical or radiographic progression in the setting of castrate testosterone levels. Treatment selection should consider prior systemic therapies, disease burden and tempo, symptom profile, comorbidities, and frailty. Molecular characterization, including evaluation for homologous recombination repair alterations and mismatch repair deficiency, is highly important for identifying candidates for PARP inhibitors or immune checkpoint blockade and other emerging biomarker-driven targeted strategies. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has emerged as a key treatment. PSMA-positron emission tomography-based selection, incorporating assessment of uptake intensity, tumor heterogeneity, and total tumor volume, may help identify patients who are most likely to benefit from this treatment. Clinical factors such as liver metastases and limited prior response to androgen receptor-directed therapy have been associated with less favorable outcomes. Early on-treatment assessment using prostate-specific antigen response and PSMA-based imaging may support adaptive treatment strategies and earlier recognition of resistance. Given the high prevalence of bone metastases, bone-protecting agents should be considered to reduce skeletal-related events. Early palliative care (EPC) is now widely recognized as a concurrent, patient-centered intervention that improves quality of life, symptom burden, coping, and satisfaction across advanced cancers. Prostate cancer represents an especially compelling setting for EPC because of prolonged advanced disease courses, cumulative symptom burden, repeated treatment transitions, and persistent unmet supportive needs.

Clinical Characteristics and Predictive Factors of Symptomatic Skeletal Events in Patients With Metastatic Castration-Sensitive Prostate Cancer Treated With Denosumab.

Intramuscular and subcutaneous tissue metastasis of prostate cancer is a rare and aggressive process. We describe the case of a 61-year-old man with metastatic castration-resistant prostate cancer who presented with growing left gluteal/proximal thigh masses during ongoing 177 Lu-PSMA-617 (Pluvicto) treatment. While post-Pluvicto imaging demonstrates markedly improved nodal and hepatic metastases, progressive development of multifocal left gluteal/proximal thigh intramuscular and subcutaneous tissue metastases suggests a heterogeneous treatment response to Pluvicto. This case shows rare soft tissue metastasis in a heterogeneous treatment response to Pluvicto.

Efficacy and safety of darolutamide in combination with androgen deprivation therapy and docetaxel in European patients from the phase 3 ARASENS trial.

There are four FDA-approved poly (ADP-ribose) polymerase inhibitors (PARPi) for treating metastatic castration-resistant prostate cancer. However, dose-limiting toxicities may reduce efficacy when treatment is de-escalated. Identifying modulators of PARPi sensitivity could enable combination strategies that enhance efficacy while minimizing toxicity. This study investigates whether Protein kinase D1 (PrKD1), recently discovered to modulate DNA repair, influences sensitivity to PARP inhibition. We used prostate cancer cell lines with altered PrKD1 expression to assess viability following olaparib and/or Compound-10, a selective PrKD1 inhibitor, treatment. Subcellular fractionation, immunoprecipitation, in silico modeling and Western blotting of lysates of cells and tumor samples harvested from patient-derived xenograft tumor engrafted mice treated with Compound-10 were used to evaluate protein expression, interaction, and localization. PrKD1-overexpressing C4-2 cells exhibited significantly increased sensitivity to growth inhibition by olaparib. Downregulation of PrKD1 in LNCaP cells conferred resistance. Biochemical inhibition of PrKD1 by Compound-10 also enhanced sensitivity. Co-immunoprecipitation experiments demonstrated that PrKD1 and PARP1 are present in the same immunocomplex, and PrKD1 transfection in C4-2 cells increased PARP1 membrane localization. Treatment of prostate cancer PDX models with Compound-10 increased PARP1 expression. In silico molecular modeling identified a site adjacent to the PARP1 WGR domain potentially binding to multiple PrKD1 domains. Our study identifies PrKD1 as a novel modulator of sensitivity to olaparib. Co-targeting PrKD1 using small molecular inhibitors may enhance olaparib efficacy at lower doses and improve PARPi tolerability and therapeutic index. The demonstration of PARP1 at the membrane is novel, introducing the possibility of targeting membranous PARP1 for theranostic applications.

Prostate cancer (PCa) has been identified as the most prevalent form of cancer among males and the third leading cause of death from cancer in the European male population. Early-stage PCa can be treated with prostatectomy and radiotherapy, whereas metastatic cases require androgen deprivation therapy and may benefit from targeted radionuclide therapy (TRT). The objective of our research is to develop and validate an automated production of [177Lu]Lu-PSMA I&T for clinical use. [177Lu]Lu-PSMA I&T is a radioligand therapy (RLT) that targets prostate-specific membrane antigen (PSMA), which is overexpressed in metastatic and castration-resistant prostate cancer. This work delineates the development and validation of analytical methodologies for the automated production of [177Lu]Lu-PSMA I&T with a GAIA-LUNA device from Elysia, in addition to the quality control measures implemented to ensure compliance with Good Manufacturing Practices and the European Pharmacopoeia. Three validation batches were produced, and the investigational medicinal product dossier was submitted to the French National Agency of Medicine and Health Products Safety (ANSM) for authorization. PSMA-I&T was radiolabeled with 177Lu using an automated radiosynthesis device, the GAIA-LUNA, from Elysia. Furthermore, we demonstrated the 72-h stability of the [177Lu]Lu-PSMA I&T preparations at room temperature, a development that facilitates the potential subcontracting of [177Lu]Lu-PSMA I&T production to other medical facilities. The findings of this study underscore the potential of [177Lu]Lu-PSMA I&T as a therapeutic option for patients with metastatic castration-resistant prostate cancer (mCRPC) who have contraindications to chemotherapy or hormonotherapy, and highlight the importance of implementing rigorous quality control measures in the development of radiopharmaceuticals.

Interleukin-23 (IL23) has been reported to drive androgen receptor (AR) and JAK2-STAT3 signaling, promoting treatment resistance and disease progression in advanced prostate cancer (PC). We evaluated the safety, tolerability, and antitumor activity of the anti-IL23 monoclonal antibody tildrakizumab in combination with the AR pathway inhibitor (ARPI) abiraterone acetate (AA) in men with ARPI-resistant metastatic castration-resistant PC (mCRPC). mCRPC patients of ECOG performance status (PS) ≤ 2, who had previously progressed on first-line ARPI therapy, were treated with tildrakizumab (100 mg, 300 mg, 600 mg; 4-weekly) in combination with AA (YonsaTM, 500 mg daily). The primary objective was to determine the recommended phase 2 dose. Secondary endpoints were elucidation of pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. No dose limiting toxicities (DLTs) were observed, nor any grade ≥ 3 adverse effects (AEs). The most common treatment-related AEs attributable to tildrakizumab were grade 1-2 fatigue (n = 3/12; 25.0%) and grade 1 nausea (n = 2/12; 16.7%). PK analyses showed no obvious drug-drug interactions. Overall, no objective responses were observed. Median progression free survival (PFS) was 3.7 months (n = 10; 95% CI 1.6-not reached) with median overall survival (OS) of 9.7 months (n = 10; 95% CI 6.9-not reached). Tildrakizumab and abiraterone acetatecombination therapy is well tolerated but did not show clinical efficacy in this small, unselected, cohort of ARPI-resistant mCRPC patients. Further study into the causes of primary resistance to IL23 targeting in mCRPC, and development of biomarkers of downstream IL23-IL23R activity, are now needed to translate IL23 blockade into the clinic.

Background Docetaxel remains a standard treatment for metastatic castration-resistant prostate cancer (mCRPC), yet reliable prognostic markers are lacking. TP53 and RB1, key tumor suppressor genes regulating cell-cycle control and genomic stability, have been linked to aggressive disease and lineage plasticity in advanced prostate cancer. We evaluated the prognostic impact of TP53 and/or RB1 alterations in mCRPC patients treated with docetaxel. Methods We retrospectively analyzed 125 mCRPC patients treated with docetaxel. Genetic alterations were assessed using the TruSight Oncology 500 v2 panel. Progression-free survival (PFS) and overall survival (OS) were analyzed according to TP53 and RB1 alteration status. Results TP53 alterations were present in 45 patients (36.0%) and RB1 alterations in 16 (12.8%). Patients with alterations in either TP53 or RB1 had significantly shorter OS (median OS = 18.10 vs. 32.23 months; HR = 1.83, 95% CI = 1.19–2.84; p = .006). Co-altered patients showed the poorest OS (median OS = 11.40 months; HR = 5.09, 95% CI = 1.97–13.19; p < .001). PFS was also shorter in patients with TP53 or RB1 alterations. Conclusion TP53 and RB1 alterations, particularly TP53/RB1 co-alteration, are associated with poor prognosis in mCRPC treated with docetaxel.

Real-world treatment durability and pain management in older adults with metastatic castration-resistant prostate cancer.

Although olaparib plus abiraterone and prednisone has significantly prolonged radiographic progression-free survival (rPFS) in metastatic castration resistant prostate cancer patients (mCRPC), little is known about the effects of this combination therapy on metastatic hormone-sensitive prostate cancer (mHSPC), especially for those with homologous recombination repair (HRR) genes. We conducted a phase II clinical trial to evaluate the efficacy and safety of olaparib plus abiraterone for mHSPC with HRR gene mutations. Thirty patients with mHSPC who had at least one HRR gene mutation were enrolled. Patients were administered Olaparib 300mg BID plus abiraterone 1000mg QD and prednisone 5mg QD. The primary endpoint was 1-year rPFS rate per PCWG3-modified RECIST 1.1 by investigator assessment, and the secondary endpoints included median rPFS, PSA response rate, PSA-PFS, ORR. A total of 30 patients administered combination therapy with mutations in 7 HRR genes. All the patients had de novo mHSPC. The median follow-up was 19.0 months. The 1-year rPFS rate was 77.7% (95% CI: 63.4-95.3%). All patients achieved PSA50 response. Among the 13 patients who had measurable disease at baseline, the confirmed ORR was 84.6% (n = 11). One patient achieved a complete response, ten patients obtained a partial response, and two had progressive disease. The treatment was well tolerated, with 8(26.6%) patients experienced≥ grade 3 treatment-related adverse events (TRAEs). Common TRAE was anemia (13 patients, 43.3%). In this phase II single-arm study, olaparib plus abiraterone and ADT showed preliminary activity and a manageable safety profile in patients with HRR-mutated mHSPC, but these findings need to be confirmed in larger phase III studies. This trial is registered with ClinicalTrials.gov, number NCT05167175.

Despite treatment advances, treatment resistance for metastatic castration resistant prostate cancer (mCRPC) is nearly universal. We studied the efficacy, safety, and pharmacokinetic properties of the combination of enzalutamide and cabazitaxel in patients with mCRPC. For phase 1, we examined the safety of combination therapy and determined the recommended Phase 2 dose. Phase 2 primary endpoint included the percentage of patients achieving a ≥ 90% PSA decline (PSA90) as a measure of response to therapy. A phase 1/2 single-arm, multi-institutional clinical trial enrolled adults with histologically confirmed progressive mCRPC without prior docetaxel or cabazitaxel chemotherapy for mCRPC. Co-administration of enzalutamide 160 mg orally once daily, cabazitaxel 25 mg/m2 IV once every 21 days, and prednisone 5 mg orally twice daily in mCRPC. Descriptive statistical analysis was used for all primary and secondary endpoints. Estimated proportions are with 95% confidence interval using exact method. The study met its primary endpoint with 61.1% (95% CI: 43.5% to 76.9%) of patients achieving PSA90. Observed toxicities were similar to those seen with either agent alone. The combination of enzalutamide and cabazitaxel exhibited robust activity with a tolerable side effects. Chemo-hormonal therapies warrant further study in mCRPC. This study of enzalutamide and cabazitaxel combination therapy in patients with advanced, pre-treated mCRPC showed promising efficacy, indicating strong rationale for further investigation. In this report we looked at outcomes for patients with metastatic prostate cancer treated at multiple institutions with enzalutamide and cabazitaxel at the same time after castration therapy alone had stopped working. We found the combination was safe and had anti-cancer effect, warranting further investigation.

The treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved in recent years towards combination therapy, enhancing survival outcomes when compared with androgen deprivation therapy (ADT) alone. However, many patients who are eligible for combination therapy are still receiving ADT monotherapy, and a significant proportion of those treated with doublet combinations still experience suboptimal outcomes. Furthermore, the value of adding docetaxel to an androgen receptor pathway inhibitor (ARPI)/ADT doublet in mHSPC has not been delineated, particularly in patients with low-volume disease, and chemotherapy toxicity and tolerability remain a major concern for patients. This review addresses the significant unmet need for additional or novel treatment strategies for mHSPC, utilizing prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in a combination regimen that uses a non-chemotherapeutic approach for the treatment of mHSPC. PSMA-targeted RLT has been shown to improve survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with ARPIs +/- taxanes and is now under evaluation for the treatment of mHSPC, given its demonstrated success in the mCRPC space. Thus, continued education on RLT and its use for patients with mHSPC is important to optimize patient care. This review provides a brief outline of the mHSPC treatment landscape, focusing on the challenges and unique considerations faced by healthcare professionals when treating these patients. We also evaluate the potential role of RLT in surmounting these challenges, discussing potential barriers and solutions to its integration as a treatment for mHSPC.

PURPOSEIn the PROpel study (ClinicalTrials.gov identifier: NCT03732820), olaparib plus abiraterone demonstrated statistically significant radiographic progression-free survival benefit versus placebo plus abiraterone in a first-line metastatic castration-resistant prostate cancer (mCRPC) population unselected by homologous recombination repair gene mutation (HRRm) status. From PROpel, we report exploratory biomarker analyses assessing HRRm and BRCA1 and/or BRCA2 (BRCAm) status using tumor tissue and plasma-derived circulating tumor (ct) DNA.METHODSPatients received (1:1) either olaparib (300 mg twice a day) or placebo in combination with abiraterone (1,000 mg once daily) plus prednisone/prednisolone (5 mg twice a day). Tumor tissue and ctDNA samples were analyzed using FoundationOne CDx and FoundationOne Liquid CDx tests, respectively. Biomarker results are presented by individual tests and as an aggregate analysis.RESULTSHRRm status was obtained for 778 of 796 (98%) patients randomly assigned. Aggregating tumor tissue and ctDNA results, 226 patients were identified as having HRRm (including 85 BRCAm). In matched tumor tissue and ctDNA samples (n = 491), and using the tumor tissue result as the reference, high concordance was observed for HRRm (overall percent agreement, 85.1%; negative predictive value, 93.7%) and BRCAm status (overall percent agreement, 93.9%; negative predictive value, 97.3%), with low ctDNA fraction being a limiting factor in rare cases where discordance was observed. Based on the observed agreement, there was a potential incidence of 1% unidentified BRCAm in aggregated non-BRCAm patients (n = 693).CONCLUSIONAggregating tumor tissue and ctDNA analyses maximized the number of patients (98%) with known biomarker status in PROpel while limiting the number of potential false negatives. This represents the most comprehensive means for identifying biomarker-positive and biomarker-negative subgroups and demonstrates the complementary utility of ctDNA testing in mCRPC, particularly when tissue testing is unable to provide a clinically useful result.

Phase I investigation of the enhancer of zeste homolog 2 inhibitor, mevrometostat, plus enzalutamide showed promising antitumor activity versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03460977). MEVPRO-1 (open label) and MEVPRO-2 (double blind) are ongoing, global, phase III, randomized studies evaluating efficacy and safety of mevrometostat plus enzalutamide in patients with mCRPC. MEVPRO-1 will include ~600 patients with ≥12 weeks of prior abiraterone treatment, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, testosterone ≤50 ng/dL, and life expectancy ≥6 months. MEVPRO-2 will include ~900 androgen receptor pathway inhibitor-naïve patients, with ECOG PS 0-1, testosterone ≤50 ng/dL, and life expectancy ≥12 months. Patients are randomized 1:1 to mevrometostat (875 mg twice daily with food) plus enzalutamide (160 mg once daily), or physician's choice of enzalutamide or docetaxel (MEVPRO-1) or enzalutamide (MEVPRO-2). Primary endpoint is radiographic progression-free survival (rPFS) per Response Evaluation Criteria in Solid Tumors 1.1 (soft tissue) and Prostate Cancer Working Group 3 criteria (bone) assessed by blinded independent central review. Overall survival is a secondary objective. Kaplan-Meier analysis will summarize time-to-event endpoints. Safety will be assessed. Results will evaluate whether mevrometostat plus enzalutamide can provide clinical benefit in patients with mCRPC.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT06551324 (MEVPRO-1) and NCT06629779 (MEVPRO-2).

In November 2020, olaparib became the first approved poly adenosine diphosphate (ADP)-ribose polymerase inhibitor (PARPi) for metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 mutations (BRCAm) in the Netherlands. As randomized clinical trials include fitter patients, their findings may not fully reflect real-world outcomes. The aim was to evaluate genomic testing practice and subsequent use and outcomes of olaparib monotherapy in a real-world BRCAm mCRPC population. Data were derived from ten hospitals in the Dutch CAPRI-3 registry, including mCRPC patients diagnosed between 2016 and 2021. Those receiving olaparib in standard-of-care treatment after its national approval (from November 2020) were analyzed and grouped as taxane-naïve (TN) or post-taxane (PT). The primary endpoint was overall survival (OS). Among 1996 mCRPC patients, genomic analysis (somatic and/or germline) was performed in 23.4% (range 3.8-63.2% across hospitals), identifying BRCAm in 11.3% of patients. Tested patients differed significantly in age, comorbidities, and prior treatment. Among 35 eligible BRCAm patients, 27 (77.1%) received olaparib. TN patients (8/27) were significantly older and initiated olaparib at an earlier line of therapy. Median OS was 28.7 months (95% confidence interval (CI) not reached) in TN versus 10.5 months (95% CI 9.6-11.5) in PT patients (p = 0.003). Limitations include the retrospective design and small subgroups. Genomic testing application remained limited and uneven across centers. Most eligible patients received olaparib; TN patients seemed to benefit most.

We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare between cohorts. Respectively, objective response rates (95% CI) were 9.3% (2.6-22.1), 19.5% (8.8-34.9), 4.5% (0.1-22.8), and 12.2% (4.1-26.2), and median radiographic progression-free survival (95% CI) was 3.9 (2.2-7.6), 4.2 (3.3-5.6), 3.5 (2.1-5.8), and 7.9 (5.6-9.3) months. Respective incidence of grade ≥3 treatment-related adverse events was 28.8%, 30.1%, 18.4%, and 34.7%. Preliminary post hoc biomarker analyses in patients who received treatment with any immunotherapy regimen (i.e., treated with either of the nivolumab plus ipilimumab regimens or with ipilimumab alone, n = 12) identified a transcriptional signature, derived from the most highly expressed genes across cell types within select perivascular immune niches (comprising CD31+ endothelial, CD14+HLA-DR+ myeloid, and CD4+ and CD8+ T cells), which was associated with prolonged overall survival. These results provide further evidence of antitumor activity with nivolumab plus ipilimumab in select patients with metastatic castration-resistant prostate cancer and nominate a candidate prognostic biomarker that warrants confirmation in future prospective clinical trials.

Unbiased combinatorial screening reveals co-inhibition of nuclear export and translation initiation as a vulnerability in metastatic castration-resistant prostate cancer. Dual targeting of XPO1 and EIF4A1 drives synergistic collapse of oncogenic protein networks, including AR/AR-V7 signaling, to overcome key resistance mechanisms and induce potent antitumor responses across heterogeneous models. Notably, these effects are achieved at substantially reduced doses using clinically tractable agents, defining a mechanistically grounded therapeutic strategy poised for rapid clinical translation.

Radium-223 is an α-emitting radiopharmaceutical that improves survival in metastatic castration-resistant prostate cancer (mCRPC). Preclinical data suggest synergy between poly(ADP-ribose) polymerase (PARP) inhibition and radiation. After phase I dose-finding, we conducted a randomized phase II trial to assess efficacy and safety of this combination versus radium-223. Men with mCRPC and ≥2 bone metastases (BM) were randomly assigned 1:1 to olaparib (200 mg twice daily) plus radium-223 (55 kBq/kg intravenous once every 4 weeks × 6 doses) or radium-223. Crossover was allowed at progression. The primary end point was investigator-assessed radiographic progression-free survival (rPFS). A total of 120 patients were randomly assigned. Most had prior androgen receptor pathway inhibitor exposure (96%), 52% had received docetaxel, 47% had >20 BM, and 90% received bone-protecting agents. The combination significantly improved rPFS (median 8.9 v 4.7 months; hazard ratio [HR], 0.50 [one-sided 90% CI, 0.35 to 0.70]; one-sided P = .0042). The benefit was most pronounced in patients without prior docetaxel (13.7 v 5.7 months; HR, 0.24 [90% CI, 0.15 to 0.40]) and those with ≤20 BM (13.4 v 4.2 months; HR, 0.21 [90% CI, 0.13 to 0.33]). The 1-year cumulative incidence of symptomatic skeletal-related events was lower with the combination (12.7% v 22.9%). Median overall survival was similar (20.2 v 21.1 months). Grade ≥3 treatment-related adverse events occurred in 56% versus 33% (combination v radium-223), primarily hematologic, including lymphopenia (31% v 9.1%), anemia (22% v 16%), and thrombocytopenia (6.8% v 3.6%). Olaparib plus radium-223 significantly prolonged rPFS compared with radium-223 in men with mCRPC and BM. Despite increased hematologic toxicity, the regimen was manageable and supports further exploration of DNA damage-targeted strategies in this population.

Expert practical recommendations for optimising tumour and germline testing of homologous recombination repair gene mutations in metastatic prostate cancer.