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Background: In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available., Methods: Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies., Results: All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1., Conclusions: Long-term darolutamide treatment was well tolerated; no new safety signals observed. In patients with mCRPC, long-term darolutamide treatment was well tolerated and no new safety signals were observed. These findings are consistent with previous reports, demonstrating a favorable safety and tolerability profile of darolutamide., (© 2023. The Author(s).)

Background: Novel therapies for metastatic castration-resistant prostate cancer (mCRPC) have improved patient outcomes. However, there is uncertainty on the optimal selection of therapeutic agents for subsequent lines of therapy., Methods: We conducted a comprehensive review of published evidence from pivotal clinical trials and recent guidelines for the treatment of mCRPC. We further identify gaps in knowledge and areas for future research., Results: Key considerations to help guide treatment selection for patients with mCRPC include personal treatment history, individual clinical characteristics, symptoms, prognosis, availability of clinical trials, and other patient-specific factors. Genetic testing and prostate-specific membrane antigen-targeted imaging are important tools to evaluate candidacy for newer therapeutic options such as poly (ADP-ribose) polymerase inhibitors, alone or in combination with androgen receptor pathway inhibitors, and [ 177 Lu]Lu-PSMA-617., Conclusion: This article provides an overview of the evolving treatment landscape of mCRPC, discussing guideline-recommended treatment options and data from key clinical trials, while highlighting ongoing trials that may impact the future treatment landscape. Recommendations for optimal treatment sequencing based on individual patient factors are provided., (© 2024. The Author(s).)

Background/objectives: Based on the SPARTAN and TITAN studies, apalutamide is approved for patients with nonmetastatic castration-resistant and metastatic castration-sensitive prostate cancer. Skin rash was a common adverse reaction across indications. We hypothesized that earlier identification and intervention could improve rash outcomes., Subjects/methods: A prespecified rash management guide outlining recommended skin care practices was provided to all patients enrolled in Apa-RP (NCT04523207). Rash-related safety data from Apa-RP were compared descriptively with data from SPARTAN and TITAN., Results: Patients in Apa-RP experienced improved rash-related outcomes vs those in SPARTAN and TITAN., Conclusions: Increased vigilance and proactive management may reduce the incidence, severity, and duration of rash during apalutamide treatment., (© 2024. The Author(s).)

Background: The real-world EPIX study was conducted to gather information about the characteristics of patients with metastatic castration-resistant prostate cancer (mCRPC) who survived ≥2 years after treatment with the alpha-emitter radium-223., Methods: This retrospective study of electronic health records in the US Flatiron database (NCT04516161) included patients with mCRPC treated with radium-223 between January 2013 and June 2019. Median overall survival (OS) and prostate-specific antigen (PSA) response (≥50% reduction) from start of radium-223 treatment were the primary and secondary endpoints, respectively. Patient characteristics were compared between those who survived ≥2 years versus <2 years, including a subgroup who survived <6 months., Results: In the 1180 patients identified, median OS was 12.9 months (95% CI: 12.1-13.7), and 13% of patients with data at 6 months had a PSA response. The survival groups included 775 patients (65.7%) who survived <2 years (including 264 (22.4%) who survived <6 months) and 185 patients (15.7%) who survived ≥2 years; 220 patients (18.6%) had incomplete follow-up data and were censored. On multivariate analysis, age >75 years, Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, visceral metastases, prior symptomatic skeletal events (SSEs), and prior chemotherapy were independently prognostic of reduced OS. For patients with survival ≥2 years versus <2 years, median age was 71 versus 75 years, 4% versus 14% had ECOG PS 2-4, 4% versus 10% had visceral metastases, 38% versus 44% had prior SSEs, and 16% versus 32% had prior chemotherapy., Conclusions: In this study of men with mCRPC treated in real-world clinical practice, median OS was consistent with that seen in the phase 3 ALSYMPCA trial. Patients who survived ≥2 years after the start of radium-223 were younger and had better ECOG PS, lower disease burden, and less use of prior chemotherapy than those who survived <2 years., (© 2022. The Author(s).)

Background: Prostate cancer (PC) is a leading cause of death in older men. Androgen deprivation therapy (ADT) is considered the standard-of-care for men with locally advanced disease. However, continuous androgen ablation is associated with acute and long-term adverse effects and most patients will eventually develop castration-resistant PC (CRPC). The recent approval of three, second-generation androgen receptor inhibitors (ARIs), apalutamide, enzalutamide, and darolutamide, has transformed the treatment landscape of PC. Treatment with these second-generation ARIs have produced positive trends in metastasis-free survival, progression-free survival, and overall survival. For patients with non-metastatic CRPC, who are mainly asymptomatic from their disease, maintaining quality of life is a major objective when prescribing therapy. Polypharmacy for age-related comorbidities also is common in this population and may increase the potential for drug-drug interactions (DDIs)., Method: This review summarizes the multiple factors that may contribute to the therapeutic burden of patients with CRPC, including the interplay between age, comorbidities, concomitant medications, the use of ARIs, and financial distress., Conclusions: As the treatment landscape in PC continues to rapidly evolve, consideration must be given to the balance between therapeutic benefits and potential treatment-emergent adverse events that may be further complicated by DDIs with concomitant medications. Patient-centered communication is a crucial aspect of alleviating this burden, and healthcare professionals (HCPs) may benefit from training in effective patient communication. HCPs should closely and frequently monitor patient treatment responses, in order to better understand symptom onset and exacerbation. Patients also should be encouraged to participate in exercise programs, and health information and support groups, which may assist them in preventing or mitigating certain determinants of the therapeutic burden associated with PC and its management., (© 2021. The Author(s).)

Background: Nonmetastatic castration-resistant prostate cancer (nmCRPC) is defined as a rising prostate-specific antigen concentration, despite castrate levels of testosterone with ongoing androgen-deprivation therapy or orchiectomy, and no detectable metastases by conventional imaging. Patients with nmCRPC progress to metastatic disease and are at risk of developing cancer-related symptoms and morbidity, eventually dying of their disease. While patients with nmCRPC are generally asymptomatic from their disease, they are often older and have chronic comorbidities that require long-term concomitant medication. Therefore, careful consideration of the benefit-risk profile of potential treatments is required., Methods: In this review, we will discuss the rationale for early treatment of patients with nmCRPC to delay metastatic progression and prolong survival, as well as the factors influencing this treatment decision. We will focus on oral pharmacotherapy with the second-generation androgen receptor inhibitors, apalutamide, enzalutamide, and darolutamide, and the importance of balancing the clinical benefit they offer with potential adverse events and the consequential impact on quality of life, physical capacity, and cognitive function., Results and Conclusions: While the definition of nmCRPC is well established, the advent of next-generation imaging techniques capable of detecting hitherto undetectable oligometastatic disease in patients with nmCRPC has fostered debate on the criteria that inform the management of these patients. However, despite these developments, published consensus statements have maintained that the absence of metastases on conventional imaging suffices to guide such therapeutic decisions. In addition, the prolonged metastasis-free survival and recently reported positive overall survival outcomes of the three second-generation androgen receptor inhibitors have provided further evidence for the early use of these agents in patients with nmCRPC in order to delay metastases and prolong survival. Here, we discuss the benefit-risk profiles of apalutamide, enzalutamide, and darolutamide based on the data available from their pivotal clinical trials in patients with nmCRPC.

Background: In this study, we evaluated real-world data on radium-223 plus abiraterone/prednisone or enzalutamide. Previously, the ERA 223 trial (NCT02043678) demonstrated increased fracture risk with concurrent treatment with radium-223 and abiraterone plus prednisone/prednisolone in patients with metastatic castration-resistant prostate cancer (mCRPC)., Methods: We used the Flatiron Health database to perform a retrospective study of patients with mCRPC treated with radium-223. Treatment with radium-223 plus abiraterone/prednisone or enzalutamide was defined as concurrent if both drugs started within 30 days of one another, or layered when the second drug started ≥30 days after the first. The index date was defined as the day of the first radium-223 dose. Outcome measures included symptomatic skeletal events (SSEs), overall survival (OS), and patterns of treatments received., Results: Of the 625 patients treated with radium-223, 22% received it together with abiraterone/prednisone and 27% with enzalutamide. When these agents were combined, they were often initiated in a layered fashion (73% layered, 23% concurrent). Prior or concomitant bone health agents (BHAs) were received by 67% and 55% of patients, respectively. Median follow-up was 9 months. Overall, incidence rates for SSEs and pathologic fractures were 0.35 and 0.11 patients per person-year, respectively. Median OS from mCRPC diagnosis was 28.1 months., Conclusions: In this real-world setting, combination treatments with radium-223 and abiraterone/prednisone or enzalutamide were common. These agents were more commonly given in a layered than a concurrent fashion. Incidence rates for SSEs were reduced when BHAs were used; however, BHAs were underutilized.

Background: Sipuleucel-T is an autologous cellular immunotherapy that is FDA approved for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC). The IMPACT registry trial demonstrated a 4.1 month survival benefit, but not a consistent PSA response or improvement in progression-free survival. Based upon several factors, including this lack of objective treatment response, sipuleucel-T has been under-utilized in this patient population, despite current NCCN recommendations., Methods: In order to explore if delayed treatment response occurs in a subset of patients, we performed a single institutional retrospective analysis of mCRPC patients treated with sipuleucel-T and ongoing ADT alone. Within that group, we then identified a subset of sipuleucel-T-treated men with long-term disease control and no additional interventions. To independently confirm this finding, we evaluated a total of 336 patients from 4 large urology group practices treated with sipuleucel-T between 2010 and 2014 and identified 44 patients who met the same criteria and demonstrated evidence of PSA stabilization post sipuleucel-T treatment., Results: For this subgroup of patients, 79% (95% CI: 64.5%, 88.1%) survived 36 months with a median time to subsequent therapy of 17.8 months (95% CI 10.3, 25.3)., Conclusions: Although patient selection could account for some or all of these results, these data support the utilization of sipuleucel-T alone in select mCRPC patients that is associated with a delay in disease progression and a good overall prognosis.

Background: Treatment options for metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years and include cytotoxic agents (e.g., docetaxel and cabazitaxel), immunotherapy (e.g., sipuleucel-T), oral hormonal therapies targeting the androgen receptor axis (e.g., enzalutamide and abiraterone), and targeted alpha therapy (e.g., radium-223 dichloride (radium-223)). Although treatment guidelines have been updated to reflect the availability of new agents, it is not easy to apply them in daily clinical practice because recommendations vary depending on patient comorbidities and disease characteristics. Furthermore, therapeutic accessibility, clinical judgment, and experience affect the selection of treatment options., Methods: In this review, we provide practical guidance for the integration of radium-223 into the management of patients with mCRPC based on our collective clinical experience, as well as the available clinical trial data., Results: Radium-223 is a targeted alpha therapy; as a bone-seeking calcium mimetic, it accumulates in hydroxyapatite areas surrounding tumor lesions and selectively binds to the areas of increased bone turnover. Radium-223 prolongs overall survival and delays time to the first symptomatic skeletal events in men with mCRPC, and is indicated for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastases. We review its clinical efficacy and safety, practical guidance on identifying the appropriate patient, and recommendations for how best to educate and inform prospective patients regarding their treatment decision making. In addition, we review recent evidence for sequential and combination therapies with radium-223, provide our experiences with these treatment approaches, and discuss their implications for the future treatment of patients with mCRPC., Conclusions: Based on our clinical experience, radium-223 should be considered relatively early in the treatment course in patients with mCRPC with bone metastases. Coordination of care among multidisciplinary team members, patients, and caregivers is essential for optimizing safe and effective treatment with all CRPC therapies.

The last few years have seen considerable evolution in treatment options and therapeutic strategies for patients with castrate-resistant prostate cancer (CRPC). One major change was the expansion of chemotherapeutic options with the approval of cabazitaxel, representing the first chemotherapeutic therapy after docetaxel to demonstrate improved survival in patients with CRPC. A number of other noncytotoxic therapies have either recently been approved or are in advanced development for treating this patient population. Offering novel mechanisms of action, these new agents make considerably more expansive and complex the decisions regarding when to treat, which agents to use, and the order in which they are administered. A pivotal decision point for urologists who treat patients with advanced prostate cancer has been timing the patient's referral to an oncologist for chemotherapy. Although clinical guidelines regard chemotherapy as only appropriate for prostate cancer patients with symptomatic metastatic disease, increasing evidence points to the possibility that a subgroup of patients may benefit from an earlier introduction of chemotherapy. At the same time, additional treatment options that may either precede chemotherapy or follow initial chemotherapeutic failure mean that urologists must closely monitor their patients' health status to match specific clinical profiles with specific treatment options. With the increase in number and variety of therapeutic approaches, the role of the urologist has been expanded, in part, owing to the opportunity for urologists to administer treatments previously unavailable, and also owing to the growing importance of working cooperatively with oncologists and as a member of a multidisciplinary team.

Androgen deprivation therapy (ADT) is first-line treatment for metastatic prostate cancer (PCa). Gonadotrophin-releasing hormone (GnRH) agonists are the most commonly used ADT but have several theoretical physiologic disadvantages (e.g. initial testosterone surge, potential microsurges upon repeat administration). Testosterone surge delays the intended serologic endpoint of testosterone suppression and may exacerbate clinical symptoms. GnRH antagonists were developed with a view toward overcoming these potential adverse physiologic events. This review evaluates GnRH agonists and antagonists, assessing the potential future role of antagonists in PCa and strategies to minimize ADT adverse events (AEs). Evidence was identified via PubMed search (by GnRH agent and other ADT-related terms), from review article bibliographies, and authors' therapy area knowledge, with articles included by author consensus. Degarelix shows similar efficacy to a GnRH agonist in achieving and maintaining castration, with faster onset and without testosterone surge/microsurges. Phase III data showed that, in the first treatment year, degarelix displayed a lower risk of PSA failure or death (composite endpoint), lower levels of the bone marker serum alkaline phosphatase (in baseline metastatic disease), and fewer musculoskeletal AEs than the agonist leuprolide. Also, crossing over from leuprolide to degarelix after 1 year reduced the risk of PSA failure or death. ADT displays an AE spectrum which can impact quality of life as well as causing significant morbidities. Strategies to improve ADT tolerability have become increasingly important including: a holistic management approach, improved diet and exercise, more specific monitoring to detect and prevent testosterone depletion toxicities, and intermittent ADT allowing hormonal recovery between treatment periods. Clinical studies suggest possible benefits of GnRH antagonists over agonists based on different mechanisms of action. GnRH antagonists should now be considered as an alternative first-line ADT option in advanced PCa. Intermittent ADT and a holistic treatment approach are promising strategies to improve ADT tolerability.

Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and is increasingly used to treat asymptomatic patients with prostate-specific antigen recurrence after failed primary therapy. Although effective, ADT is associated with multiple adverse effects, many of which are related to the estrogen deficiency that occurs as a result of treatment. These include increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss. By providing clinicians with a greater awareness of the estrogen deficiency induced adverse effects from ADT, they can proactively intervene on the physical and psychological impact these effects have on patients.