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Darolutamide, an androgen receptor inhibitor, has been approved by the Food and Drug Administration (FDA) for the treatment of prostate cancer (PCa), especially for patients with androgen receptor mutations. Owing to the unique lipidomic profile of PCa and the effect of darolutamide, the relationship between darolutamide and ferroptosis remains unclear. The present study showed that darolutamide significantly induces ferroptosis in AR PCa cells. Mechanistically, darolutamide promotes ferroptosis by downregulating SREBP1, which then inhibits the transcription of FASN. FASN knockdown modulates phospholipid remodeling by disrupting the balance between polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs), which induces ferroptosis. Clinically, SREBP1 and FASN are significantly overexpressed in PCa tissues and are related to poor prognosis. Moreover, the synergistic antitumor effect of combination therapy with darolutamide and ferroptosis inducers (FINs) was confirmed in PCa organoids and a mouse xenografts model. Overall, these findings revealed a novel mechanism of darolutamide mediated ferroptosis in PCa, laying the foundation for the combination of darolutamide and FINs as a new therapeutic strategy for PCa patients.

Abstract Context With new treatment strategies approved in metastatic hormone-sensitive prostate cancer (mHSPC), heterogeneity across trials hinders the physicians’ choice for first-line treatment. Objective We conducted a systematic review and network meta-analysis to assess the efficacy of currently approved treatments for mHSPC stratifying patients according to their disease burden (high- vs. low-volume as per CHAARTED criteria) and onset of metastatic disease (synchronous vs. metachronous). Intervention Eleven randomized controlled trials (RCTs) published until October 30, 2024 were included. Treatment regimens were grouped as triplets for combinations of docetaxel, androgen receptor pathway inhibitors (ARPIs) and androgen-deprivation therapy (ADT), separate doublets for docetaxel plus ADT, ARPI plus ADT, or monotherapy for ADT alone. Outcome Measurements and Statistical Analysis Overall survival (OS) and radiographic progression-free survival (rPFS) outcomes were collected. OS as primary endpoint, and rPFS as secondary endpoint, were analyzed separately in high- and low-volume patients. Additional subgroup analyses accounted for timing of metastases categorized as high-volume/synchronous, high-volume/metachronous, low-volume/synchronous, and low-volume/metachronous disease. Evidence Synthesis Triplet combinations prolonged significantly OS and rPFS in high-volume disease (P-score 0.99), and high-volume/synchronous disease (P-score 0.99). ARPI/ADT doublets performed best in low-volume patients (P-score 0.94), and low-volume/metachronous (P-score 0.99). In the high-volume/metachronous population, triplets, and doublets were equally effective. Conclusions The results provide collective evidence for treatment selection based on disease volume and timing of metastasis with strongest survival benefits of triplets for high-volume/synchronous mHSPC patients and of ARPI doublets for low-volume disease.

Abstract The second-generation antiandrogens have achieved an ever-growing list of approvals and indications in subsets of prostate cancer. Here, we provide an overview of second-generation antiandrogen trials and FDA approvals and outline a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer. All published phase II-III randomized controlled trials reporting outcomes with the use of second-generation antiandrogens in prostate cancer are included as well as all published trials and retrospective studies of second-generation antiandrogen sequencing and/or combinations. Complete tabular and graphical representation of all available evidence is provided regarding the use and sequencing of second-generation antiandrogens in prostate cancer. In metastatic castration-resistant prostate cancer, evidence suggests prioritization of abiraterone before chemotherapy, chemotherapy after second-generation antiandrogen failure, and postchemotherapy enzalutamide in select patients to maximize agent efficacy and tolerability. We conclude that a rational, optimized sequencing of second-generation antiandrogens with other treatment options is feasible with present data. Considering the available data, this article provides an overview of second-generation antiandrogen trials and FDA approvals and outlines a rational sequencing approach for the use of these agents as they relate to chemotherapy and other available treatment modalities in advanced prostate cancer.

Enzalutamide is the first second-generation nonsteroidal androgen receptor (AR) antagonist with a strong binding affinity to AR. Most significantly, enzalutamide can prolong not only overall survival time and metastatic free survival time for patients with lethal castration-resistant prostate cancer (CRPC), but also castration-resistant free survival time for patients with castration-sensitive prostate cancer (CSPC). Enzalutamide has thus been approved by the US Food and Drug Administration (FDA) for the treatment of both metastatic (in 2012) and non-metastatic (in 2018) CRPC, as well as CSPC (2019). This is an inspiring drug discovery story created by an amazing interdisciplinary collaboration. Equally important, the successful clinical use of enzalutamide proves the notion that the second-generation AR antagonists can serve as hormonal therapeutics for three forms of advanced prostate cancer. This has been further verified by the recent FDA approval of the other two second-generation AR antagonists, apalutamide and darolutamide, for the treatment of prostate cancer. This review focuses on the rational design and discovery of these three second-generation AR antagonists, and then highlights their syntheses, clinical studies, and use. Strategies to overcome the resistance to the second-generation AR antagonists are also reviewed.

Management of non-metastatic castration-resistant prostate cancer (nmCRPC) has undergone a paradigm shift with next-generation androgen receptor inhibitors. However, direct comparative data are not available to inform treatment decisions and/or guideline recommendations. Therefore, we performed network meta-analysis to indirectly compare the efficacy and safety of currently available treatments. Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or metastasis-free and/or prostate-specific antigen (PSA) progression-free survival (OS/MFS/PSA-PFS) and/or adverse events (AEs) in nmCRPC patients were considered eligible. Three studies (n = 4117) met our eligibility criteria. Formal network meta-analyses were conducted. For MFS, apalutamide, darolutamide, and enzalutamide were significantly more effective than placebo, and apalutamide emerged as the best option (P score: 0.8809). Apalutamide [hazard ratio (HR): 0.85, 95% credible interval (CrI): 0.77–0.94] and enzalutamide (HR: 0.86, 95% CrI: 0.78–0.95) were both significantly more effective than darolutamide. For PSA-PFS, all three agents were statistically superior to placebo, and apalutamide emerged as the likely preferred option (P score: 1.000). Apalutamide (HR: 0.71, 95% CrI: 0.69–0.74) and enzalutamide (HR: 0.76, 95% CrI: 0.74–0.79) were both significantly more effective than darolutamide. For AEs (including all AEs, grade 3 or grade 4 AEs, grade 5 AEs, and discontinuation rates), darolutamide was the likely best option. Apalutamide and enzalutamide appear to be more efficacious agents for therapy of nmCRPC, while darolutamide appears to have the most favorable tolerability profile. These findings may facilitate individualized treatment strategies and inform future direct comparative trials.

The oncogenic activation of the PI3K/AKT/mTOR (PAM) pathway, which is often associated with loss of PTEN, is an important adaptive mechanism to androgen-targeted therapy in castration-resistant prostate cancer (CRPC). The concomitant targeting of the PAM pathway and the androgen receptor (AR) pathway is a promising therapeutic strategy for CRPC. Many PAM pathway inhibitors only target one component of the PAM pathway, which can limit efficacy due to the activation of the uninhibited components. We previously showed that the multi-target pan-PI3K-mTORC1/2 inhibitor, gedatolisib, exerts greater growth-inhibitory effects than single-target PAM pathway inhibitors in prostate cancer (PC) cells, regardless of PTEN or AR status. In the present study, we investigated the molecular and cellular effects of gedatolisib in combination with darolutamide in both PTEN+ and PTEN-deficient PC cell lines, including AR+ PC cell lines adapted to long-term treatment with darolutamide. We found that the gedatolisib + darolutamide combination exerted greater anti-proliferative and cytotoxic effects than the single agents in most AR+ PC cell models, regardless of their PTEN status. The gedatolisib + darolutamide combination inhibited AR and PAM pathway activities, blocked cell cycle progression, induced apoptotic cell death, and reduced glucose and lipid metabolism. The drug combination was effective in both darolutamide-naïve and darolutamide-adapted cell lines, suggesting potential benefit in prostate tumors that progressed after androgen-targeted therapy. These results provide a strong rationale for clinical studies evaluating gedatolisib in combination with AR inhibitors in CRPC.

With the advent of new therapeutic modalities, management of metastatic castrate-sensitive prostate cancer (mCSPC) has been in flux. From androgen-deprivation therapy to docetaxel to androgen receptor-signaling inhibitors, each agent has heralded a new treatment paradigm. As such, the optimal first-line therapy for mCSPC remains incompletely defined. This review provides a narrative of recent advances to systemic therapy within the mCSPC treatment space, particularly with regard to expansion to triplet therapy.

Nonmetastatic castration-resistant prostate cancer (nmCRPC) represents a condition in which patients with prostate cancer show biochemical progression during treatment with androgen-deprivation therapy (ADT) without signs of radiographic progression according to conventional imaging. The SPARTAN, ARAMIS and PROSPER trials showed that apalutamide, darolutamide and enzalutamide, respectively, prolong metastasis-free survival (MFS) and overall survival (OS) of nmCRPC patients with a short PSA doubling time, and these antiandrogens have been recently introduced in clinical practice as a new standard of care. No direct comparison of these three agents has been conducted to support treatment choice. In addition, a significant proportion of nmCRPC on conventional imaging is classified as metastatic with new imaging modalities such as the prostate-specific membrane antigen positron emission tomography (PSMA-PET). Some experts posit that these “new metastatic” patients should be treated as mCRPC, resizing the impact of nmCRPC trials, whereas other authors suggest that they should be treated as nmCRPC patients, based on the design of pivotal trials. This review discusses the most convincing evidence regarding the use of novel antiandrogens in patients with nmCRPC and the implications of novel imaging techniques for treatment selection.

First-line treatment options for patients with metastatic hormone-sensitive prostate cancer (HSPC) are divided into two groups: androgen receptor signaling inhibitor (ARSI)-based doublet therapy and triplet therapy (which includes chemotherapy in addition to doublet therapy). However, differences in therapeutic efficacy between the two groups remain unclear. The aim of the study was to perform a comparative analysis between the two groups and to identify predictors of treatment response. We retrospectively recruited 500 patients with mHSPC treated with doublet or triplet therapy from our hospital and affiliated hospitals between 2013 and 2025. The cohort of patients with mHSPC treated with doublet therapy received ABI, ENZ, or APA in combination with a luteinizing hormone-releasing hormone analog, such as androgen deprivation therapy (ADT). The cohort of those treated with triplet therapy received darolutamide plus ADT and docetaxel. Cox proportional hazards regression analysis was performed to identify prognostic factors of overall survival in patients with mHSPC. Propensity score matching was used to adjust the clinical background of patients. The outcome (prostate-specific antigen-progression-free survival, second progression-free survival, and overall survival (OS)) of triplet therapy was significantly better than that of doublet therapy in matched high-risk patients with mHSPC. Univariate and multivariate analyses of OS in matched patients with high-risk mHSPC treated with triplet or doublet therapy suggested that treatment choice (triplet or doublet), pretreatment LDH levels, and presence of Gleason pattern 5 influenced OS in patients with high-risk mHSPC. Subgroup analysis suggested that LDH levels and the presence of Gleason pattern 5 may be predictive factors of the treatment of patients with mHSPC. Our results showed that triplet therapy achieved a better outcome than doublet therapy in patients with mHSPC.

Introduction: Treatment options for refractory prostate-specific membrane antigen (PSMA)-negative liver metastases from metastatic castration-resistant prostate cancer (mCRPC) are limited and challenging. This case report presents our clinical observation of a sustained response to a novel combination of metronomic cyclophosphamide (mCyc) and darolutamide in a 65-year-old male with heavily treated PSMA-negative mCRPC with rapid disease progression. Case Presentation: The patient was initially diagnosed 4 years prior to our evaluation with metastatic prostate cancer and treated with androgen deprivation therapy with leuprolide, enzalutamide, and definitive external beam radiation therapy to the prostate and pelvic lymphadenopathy, along with stereotactic body radiation to oligometastatic bone disease. Upon progression to mCRPC, he received abiraterone with prednisone followed by docetaxel with prednisone, both of which resulted in temporary disease stabilization but eventual rapid progression with deterioration in performance status. Given the lack of effective, tolerable options, a combination of mCyc and darolutamide was initiated. The patient demonstrated an impressive clinical response, including significant radiographic response in liver metastatic disease, an 80% reduction in prostate-specific antigen levels, and improved quality of life with resolution of all cancer-related symptoms without significant treatment-related toxicities, with ongoing response. Conclusion: This report highlights the complex challenges of managing mCRPC with PSMA-negative liver metastases. mCyc with darolutamide may represent a valuable therapeutic option for elderly patients with multiple comorbidities who have exhausted standard treatment options. However, further research is needed to establish the efficacy and safety of this combination in broader populations.