Nonmetastatic Castration-resistant Prostate Cancer Research Articles

The Effect of Apalutamide on Thyroid Function in Prostate Cancer Patients

Abstract Context Apalutamide (APT) is a nonsteroidal anti-androgen medication used to treat metastatic castrate sensitive and non-metastatic castrate-resistant prostate cancer. Early clinical trials of APT identified thyroid dysfunction as a common adverse effect of therapy, but the clinical presentation and management of APT-induced hypothyroidism has not been studied. Methods We report a case series of 16 patients with APT-associated thyroid dysfunction during prostate cancer treatment at two academic medical centers. Patient clinical parameters, thyroid function laboratory data, and thyroid hormone requirements over the course of APT treatment were analyzed. Results Among the 16 patients in our case series with APT-associated hypothyroidism, 3 had no prior thyroid disease and 13 had pre-existing hypothyroidism. The patterns of thyroid dysfunction included overt and subclinical hypothyroidism. The median time from APT initiation to thyroid function test abnormality was 19 weeks, but occurred in some cases as early as 2-4 weeks. Hypothyroidism was effectively managed with thyroid hormone replacement using levothyroxine (LT4), though some patients with pre-existing hypothyroidism required a 2- to 3-fold dose increase while on APT to achieve euthyroid state. In the subset of patients who completed or stopped APT therapy, TSH fell at a median of 11 weeks post-APT therapy and thyroid hormone requirements decreased to near pre-APT levels. Conclusion APT-associated thyroid dysfunction presents as new or worsening hypothyroidism and should prompt initiation or increase in thyroid hormone replacement. Monitoring of thyroid function tests is recommended every 1-2 months for all patients on APT and 2-3 months after completion of APT.

Physician preferences for nonmetastatic castration-resistant prostate cancer treatment in China

IntroductionThe treatment preferences of Chinese physicians who treat nonmetastatic castration-resistant prostate cancer (nmCRPC) and how they weigh the benefits and risks of nmCRPC treatment are still unknown. This study aimed to evaluate Chinese physicians’ benefit–risk treatment preferences for nmCRPC and assist in setting nmCRPC treatment goals.MethodsA paper-based discrete choice experiment (DCE) survey was administered to 80 nmCRPC-treating physicians. DCE responses were analyzed to produce the preference weight and the relative importance score for each attribute level. The marginal rate of substitution (MRS) was used to quantify the amount of overall survival (OS) physicians were willing to trade for a reduction in treatment-related adverse events (AEs). We further conducted the exploratory analysis, stratifying physicians from 5 perspectives into different subgroups and examining the treatment preferences and OS trade-off in each subgroup.ResultsIn terms of efficacy attributes, physicians placed greater emphasis on OS than time to pain progression. With regard to safety attributes, serious fracture was perceived as the most important AE by physicians, followed by serious fall, cognitive problems, skin rash, and fatigue. In the exploratory analysis, we found generally that physicians with less clinical practice experience and those from more economically developed regions placed more emphasis on AEs and were willing to give up more of their patients’ OS to reduce the risk of AEs.ConclusionPhysicians from mainland China value the importance of minimizing treatment-related AEs when considering different treatment options for patients with nmCRPC, and they are willing to trade a substantial amount of OS to avoid AEs.

Effectiveness and safety of enzalutamide and apalutamide in the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC): a multicenter retrospective study.

Phase III clinical trials demonstrated the efficacy of enzalutamide and apalutamide in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and PSA doubling time ≤10months. Although these drugs have been shown to vary in their adverse event (AE) profiles, the differences in their efficacy profiles remain to be evaluated. Therefore, this retrospective study was conducted to evaluate the efficacy of these drugs in patients with nmCRPC. This study evaluated 191 patients with nmCRPC treated with enzalutamide (n = 137) or apalutamide (n = 54) in the first-line setting at Jikei University Hospital or its affiliated hospitals between May 2014 and November 2022. Endpoints were defined as oncological outcomes (i.e., PSA response, PFS, PSA-PFS, MFS, CSS, and OS) and AEs. No significant differences were noted in patient backgrounds between the two groups. Patients exhibiting a maximum PSA response of >50% and >90% accounted for 74.5% and 48.9% of patients in the enzalutamide group, and 75.9% and 42.6% of patients in the apalutamide group, respectively, with no significant difference between the groups. The median PSA-PFS was 10months in the enzalutamide group but not in the apalutamide group, with no significant difference between the groups (P = 0.48). No significant differences were observed in MFS, CSS, or OS between the groups. Patients reporting AEs of all grades and grade 3 or higher accounted for 56.2% and 4.3% of those in the enzalutamide group and 57.4% and 7.4% of those in the apalutamide group, respectively. The most common AE was fatigue (26.3%) in the enzalutamide group and skin rash (27.8%) in the apalutamide group. In this retrospective study of their efficacy and safety, enzalutamide and apalutamide were shown to exhibit comparable oncological outcomes but quite different AE profiles, suggesting that their differential use may be warranted based on these findings.

Drug–drug interaction potential among patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) treated with novel androgen receptor inhibitors

ABSTRACT Background Nonmetastatic castration-resistant prostate cancer (nmCRPC) patients are often older and use concurrent medications that increase the potential for drug–drug interactions (pDDIs). This study assessed pDDI prevalence in real-world nmCRPC patients treated with apalutamide, darolutamide, or enzalutamide. Research design and methods Castrated prostate cancer patients without metastases prior to androgen receptor inhibitor initiation were identified retrospectively via Optum Clinformatics Data Mart claims data (8/2019–3/2021). The top 100 concomitant medications were assessed for pDDIs. Results Among 1,515 patients (mean age: 77 ± 8 years; mean Charlson Comorbidity Index: 3 ± 3), 340 initiated apalutamide, 112 darolutamide, and 1,063 enzalutamide. Common concomitant medication classes were cardiovascular (80%) and central nervous system (52%). Two-thirds of the patients received ≥5 concomitant medications; 30 (30/100 medications) pDDIs were identified for apalutamide and enzalutamide each and 2 (2/100 medications) for darolutamide. Most pDDIs had risk ratings of C or D, but four for apalutamide were rated X. Approximately 58% of the patients on apalutamide, 5% on darolutamide, and 54% on enzalutamide had ≥1 identified pDDI. Conclusions Results showed a higher frequency of pDDIs in patients receiving apalutamide and enzalutamide vs darolutamide. The impact of these could not be determined retrospectively. DDI risk should be carefully evaluated when discussing optimal therapy for patients with nmCRPC.

A Real World Observational Study Characterizing Patients With Advanced Prostate Cancer Treated With or Without Androgen Receptor-Pathway-Inhibitor Therapies in Alberta, Canada

BackgroundData are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. MethodsThis retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or nonmetastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. ResultsThis study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive 38.47 (95% CI = 32.84-NA). vs. 34.19 (95% CI = 33.33-38.83; P = .03), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. ConclusionsOutcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

A practical guide for the use of apalutamide for non-metastatic castration-resistant prostate cancer in Australia.

Studies of patients with castrate-resistant prostate cancer at high risk of developing overt metastases but with no current evidence of evaluable disease on computed tomography or bone scan non-metastatic castrate-resistant prostrate cancer have demonstrated increased metastasis-free survival and overall survival following treatment with the next-generation oral anti-androgen apalutamide (in addition to therapies that aim to lower testosterone to castrate levels) or luteinizing hormone-releasing hormone antagonist or surgical castration. Patients receiving apalutamide can be managed by medical oncologists, radiation oncologists, or urologists, preferably as part of a multidisciplinary team. However, the importance of additional safety monitoring for significant adverse effects and drug interactions should not be underestimated. The toxicities of apalutamide are manageable with experience and should be managed proactively to minimize their impact on patients. Monitoring of patients for apalutamide-specific toxicities, including skin rash, hypothyroidism, and QT prolongation should be carried out regularly, particularly in the first few months following initiation. Monitoring should continue alongside monitoring for toxicities of androgen deprivation, including cardiovascular risk, hot flashes, weight gain, bone health, muscle wasting, and diabetic risk. This review is a practical guide to the use of apalutamide describing the management of patients including dosing and administration, toxicities, potential drug interactions, and safety monitoring requirements.

Role of enzalutamide in primary and recurrent non-metastatic hormone sensitive prostate cancer: a systematic review of prospective clinical trials.

Enzalutamide, a second-generation androgen receptor inhibitor, is indicated for the treatment of metastatic disease, as well as in the treatment of non-metastatic castration resistant prostate cancer (PCa). This systematic review aims to determine outcomes and toxicity in patients with non-metastatic castration sensitive prostate cancer (nmCSPC) treated with enzalutamide in the primary or salvage settings. We performed a systematic review focusing on the role of Enzalutamide in the treatment of nmCSPC, using the PubMed/Medline database. Articles focusing on androgen receptor inhibitors in nmCSPC were included, while articles discussing exclusively metastatic or castration-resistant PCa were excluded. The initial search retrieved 401 articles, of which 15 underwent a thorough assessment for relevance. Ultimately, 12 studies with pertinent outcomes were meticulously examined. Among these, seven studies were dedicated to the investigation of enzalutamide in the primary setting, while the remaining five publications specifically addressed its use in salvage settings. Regardless of the treatment setting, our data revealed two distinct therapeutic strategies. The first advocates for the substitution of enzalutamide for androgen deprivation therapy (ADT), based on the premise of achieving equivalent, if not superior, oncological outcomes while minimizing treatment-related toxicity. The second, adopting a more conventional approach, entails augmenting the effectiveness of ADT by incorporating enzalutamide. Enzalutamide has considerable potential as a therapeutic strategy for nmCSPC, either used alone or in combination with ADT in the primary or in the salvage settings. The use of enzalutamide instead of ADT is an appealing strategy. However, more trials will be required to further understand the efficacy and side-effect profile of enzalutamide monotherapy.

The treatment landscape of nonmetastatic castrate resistant prostate cancer: A contemporary perspective

ObjectivesThe incidence of nonmetastatic castrate resistant prostate cancer (nmCRPC) is not well defined in contemporary practice. The aim of this study is to describe the incidence and patterns of treatment of nmCRPC over the last 6 years at a single high-volume Australian health institution. Subjects and methodsAll men newly diagnosed with prostate cancer at Western Health, Melbourne from January 2016 to December 2021 were included in the study. Those diagnosed with nonmetastatic prostate cancer and treated with medical or surgical castration for biochemical failure post attempted curative therapy were retrospectively reviewed for signs of castration resistance using prostate specific antigen (PSA) and testosterone biochemical markers up until October 2022. ResultsFrom January 2016 to December 2021, 822 patients were diagnosed with prostate cancer, 590 had localized disease, 373 underwent definitive locoregional therapy, and 31 went on to have biochemical recurrence and were commenced on androgen deprivation therapy. Twenty-five patients had undetectable PSA levels and were classified as having nonmetastatic castrate sensitive prostate cancer (nmCSPC), whilst the remaining 6 patients experienced a rising PSA and were thus classified as nmCRPC. The incidence rate of nmCRPC was 228 cases per 100,000 person-years.The median age at the time of prostate biopsy was 74 years (interquartile range [IQR] 64–79) in the nmCRPC group and 62 years (IQR 57–69) in the nmCSPC group. The median prebiopsy PSA (ng/ml) in the nmCRPC and nmCSPC groups were 27.5 (IQR 19.9–50.4), and 16.5 (IQR 9.0–26.0), respectively. The median duration from prostate cancer diagnosis to onset of nmCRPC was 24 months (IQR 17–29) and the median PSA doubling time was 3.4 months (IQR 2.2–5.7). ConclusionsThus, nmCRPC is an uncommon disease. Further population-based studies are required to better understand the incidence of nmCRPC.

Abstract 688: Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models

Abstract Radium-223 dichloride (radium-223) is a targeted alpha therapy that binds to newly formed abnormal bone in bone metastases and induces DNA double-strand breaks (DSBs) in cancer cells, osteoblasts and osteoclasts. Radium-223 is used for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). Darolutamide is an androgen receptor inhibitor indicated for patients with metastatic hormone-sensitive prostate cancer or non-metastatic CRPC. We studied the antitumor effects of radium-223 in combination with darolutamide using LNCaP human prostate cancer cells in vitro and an intratibial LNCaP model mimicking prostate cancer metastasized to bone. The in vitro antiproliferative effects of radium-223 and darolutamide were determined using LNCaP cells. Gene set enrichment analysis (GSEA) was conducted on RNA sequencing data from LNCaP cells treated with the synthetic androgen R1881 alone or in combination with darolutamide. LNCaP cells were inoculated into the right tibia of male NOD.scid mice. The mice (n=7-9/group) were randomized based on serum prostate-specific antigen (PSA) and treated with vehicle, radium-223 (330 kBq/kg, Q4Wx2, i.v.), darolutamide (100 mg/kg, BID, p.o.), or with a combination of radium-223 and darolutamide, for 41 days. PSA and the bone turnover markers PINP and CTX-I were measured every second week in serum. Tumor-induced abnormal bone area, bone formation rate and radium-223 uptake in tumor-bearing tibiae were determined by X-ray, histomorphometry and gamma counter, respectively. The combination of radium-223 and darolutamide showed synergistic antiproliferative effects with combination indexes between 0.69-0.75 in vitro. GSEA demonstrated a prominent darolutamide-induced downregulation of DNA damage response (DDR) signaling pathways. In vivo, the combination treatment showed synergistic antitumor efficacy (p=0.04) as demonstrated by lower PSA concentrations when compared with the vehicle, radium-223 or darolutamide monotherapies (p=0.004, p=0.011 and p=0.002, respectively). In the vehicle and combination treatment groups, the mean serum PSA was 541% and 95.9% of the pre-treatment level, respectively. Furthermore, radium-223 alone or in combination with darolutamide inhibited increased bone turnover, tumor-induced abnormal bone growth and trabecular bone formation when compared to vehicle. Concurrent administration of darolutamide did not affect radium-223 uptake in tibiae. Radium-223 in combination with darolutamide exhibited synergistic antitumor efficacy both in vitro and in vivo. The synergistic effects could be due to the radiosensitization of cancer cells by darolutamide-induced downregulation of DDR pathways. Our results suggest that the combination of targeted alpha therapy with an androgen receptor inhibitor is a promising treatment strategy for mCRPC. Citation Format: Christoph A. Schatz, Mari I. Suominen, Andreas Schlicker, Matias Knuuttila, Esa Alhoniemi, Sanna-Maria Käkönen, Bernard Haendler, Urs B. Hagemann, Arne Scholz. Radium-223 in combination with darolutamide exhibits synergistic antitumor efficacy in LNCaP prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 688.

A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer.

With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics. A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations. Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging. Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. ClinicalTrials.gov identifier NCT02200614.

Treatment patterns and healthcare resource utilization in patients with metastatic hormone-sensitive prostate cancer and nonmetastatic castration-resistant prostate cancer in China: a real-world observational study

Aim This study assessed the treatment patterns, healthcare resource utilization (HRU), costs, and annual prevalence and incidence of metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) in China. Methods A retrospective study was conducted using electronic medical records (EMR) of patients with prostate cancer from three tertiary-care hospitals in China between January 2014 and March 2021. Descriptive statistics were used to analyze study outcomes. Results In total, 1086 patients with mHSPC and 679 patients with nmCRPC were included. From 2015 to 2020, the annual percentage of prevalent and incident cases of mHSPC decreased from 22.4% to 20.0% and 11.1% to 6.9%, respectively; for nmCRPC, these increased from 3.8% to 13.6% and 3.3% to 8.4%. Androgen-deprivation therapy and first-generation antiandrogens (bicalutamide or flutamide) were the most frequently prescribed prostate cancer–related medications at baseline and follow-up in patients with mHSPC. Bicalutamide was the most frequently prescribed prostate cancer–related medication during follow-up in patients with nmCRPC. For mHSPC, inpatient admission costs were the highest, with the median (interquartile range) costs per person-month being USD 403.00 (USD 85.50–1226.20), whereas outpatient visit costs were the highest for nmCRPC (USD 372.60 [USD 139.50–818.50]). Limitations EMR-based study design did not capture treatment patterns, HRU and associated costs, and healthcare encounters that occurred outside of participating hospitals, which could have led to underestimation of the true disease burden. Conclusions A contrasting trend of a decline in the prevalence and incidence of mHSPC and an increase in these for nmCRPC was observed between 2015 and 2020 in China. Androgen-deprivation therapy and first-generation antiandrogens were the most frequently prescribed prostate cancer–related medications. Healthcare resource utilization was driven by inpatient costs in mHSPC and outpatient costs in nmCRPC.

How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.

Interaction of age and benefit of treatment intensification in advanced prostate cancer: An aggregate meta-analysis of 14 randomized trials.

118 Background: Treatment intensification (TI) for men with advanced prostate cancer consistently demonstrates improvements in overall survival (OS) when compared to androgen deprivation therapy (ADT) alone. However, TI increases morbidity and may contribute to worsening other-cause mortality. Herein, we aim to determine if there is an interaction of age and TI on OS in men with advanced prostate cancer. Methods: A systematic literature search in MEDLINE, Embase, and conference proceedings were searched to identify contemporary randomized phase 3 trials in advanced prostate cancer evaluating the role of TI with chemotherapy and/or androgen receptor-signaling inhibition (ARSI) between 1/1/2010-9/1/2023. Trials in metastatic hormone-sensitive prostate cancer (mHSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC) were included given potential for competing risks; mCRPC trials were excluded. Meta-analyses were performed with random-effect modeling. Meta-regression was performed using Hartung-Knapp methods in mHSPC trials accounting for drug (docetaxel, abiraterone acetate/prednisone (AAP), non-AAP ARSIs (apalutamide, enzalutamide, or darolutamide)), use of RT to primary, percent high volume disease, percent synchronous metastatic disease, and median PSA. Age was dichotomized as < or ≥ 70 in 8 trials, and < or ≥ 65 in 6 trials. Results: Fourteen trials with 16 randomized comparisons (n=17,765 patients) were included. A total of 9,229 younger and 7,458 older men were included in age-specific analyses. Overall, TI significantly improved OS (HR 0.72, 95%CI 0.69-0.76, p<0.0001), which was consistent irrespective of disease state (mHSPC HR 0.72, 95%CI 0.78-0.77; nmCRPC HR 0.74, 95%CI 0.66-0.83). There was a significant interaction between age and TI on OS (p-interaction <0.001); TI in younger men significantly improved OS (HR 0.65, 95%CI 0.59-0.72, p<0.0001). Older men derived less benefit from TI, but TI did improve OS (HR 0.80, 95%CI 0.74-0.87, p<0001). In subgroup of older men in mHSPC trials, a significant treatment effect difference based on drug class was observed (p=0.047); AAP (HR 0.92, 95%CI 0.78-1.10, p=0.38), docetaxel (HR 0.86, 95%CI 0.70-1.05, p=0.13), and non-AAP ARSIs (HR 0.71, 95%CI 0.63-0.81, p<0.001). On meta-regression of mHSPC trials, age remained an independent variable associated with TI benefit (p=0.005). Limitations include the post-hoc nature of this aggregate meta-analysis and use of dichotomized age. Conclusions: TI improves OS for men with mHSPC and nmCRPC, but a significant interaction between age and TI on OS was identified. Further work leveraging individual patient data is needed to understand drivers of this observation, including impact of treatment compliance, comorbid conditions, adrenal suppression, outcomes in different prognostic groups, and competing risks in older patients.

Real-world effects of novel androgen receptor axis-targeted agents on oncological outcomes in non-metastatic castration-resistant prostate cancer: A multi-institutional retrospective study.

142 Background: The benefits of novel androgen receptor axis-targeted agents (ARATs) on oncological outcomes in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in real-world settings are unclear. Methods: This multi-institutional retrospective study included 178 patients with nmCRPC treated between September 2003 and August 2022. Patients were divided into two groups: those who were treated with any novel ARATs, including apalutamide, enzalutamide, darolutamide, and abiraterone acetate, during any line of nmCRPC treatment (novel ARATs group) and those who were not (control group). Multivariable Cox proportional hazards regression analyses were performed to evaluate the effects of novel ARATs on metastasis-free survival (MFS) and overall survival (OS). Results: The median age and follow-up period after nmCRPC diagnosis were 76 years and 37 months, respectively. Of the 178 patients, 122 (69%) were treated with novel ARATs after nmCRPC diagnosis. The MFS and OS in the novel ARATs group were significantly longer than those in the control group ( P < 0.001 and P = 0.020, respectively). In multivariable analyses, a prostate-specific antigen doubling time (PSADT) of < 3 months and novel ARATs were independently and significantly associated with MFS and OS (Table). The effects of novel ARATs on MFS were consistently observed across subgroups stratified by age (< 75 years or ≥ 75 years), history of radical treatment (no or yes), biopsy Gleason score (< 9 or ≥ 9), clinical stage (≤ cT3 and cN0, or cT4 or cN1), and PSADT (≥ 3 months or < 3 months). Conclusions: Novel ARATs were significantly associated with improved oncological outcomes in patients with nmCRPC in a real-world setting, regardless of tumor aggressiveness. [Table: see text]

Enzalutamide versus Abiraterone Plus Prednisolone for Nonmetastatic Castration-Resistant Prostate Cancer: A Sub-Analysis from the ENABLE Study for PCa

Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22–2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35–1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19–2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC.

Improving the identification of high-risk non-metastatic castration-resistant prostate cancer patients in clinical practice.

Non-metastatic castration-resistant prostate cancer (nmCRPC) represents a challenging disease state in prostate cancer care. nmCRPC patients with a high risk of progression to metastatic disease who are identified by a prostate-specific antigen doubling time (PSADT) ≤10 months are eligible for treatment with the novel androgen receptor inhibitors (ARIs), shown to delay disease progression and extend survival. However, nmCRPC is often unexploited in clinical practice due to a lack of standardization in the methodology and in the tools used for its identification. In this article, a group of Urology and Oncology specialists with acknowledged expertise in prostate cancer reviews the state of the art in the management of high-risk nmCRPC patients, identifies gaps and unmet needs, and proposes strategies to optimize the identification of this patient subgroup in the clinical practice and improve their health outcomes.

Prostate cancer management in Southeast Asian countries: a survey of clinical practice patterns.

Prostate cancer (PC) has a serious public health impact, and its incidence is rising due to the aging population. There is limited evidence and consensus to guide the management of PC in Southeast Asia (SEA). We present real-world data on clinical practice patterns in SEA for advanced PC care. A paper-based survey was used to identify clinical practice patterns and obtain consensus among the panelists. The survey included the demographics of the panelists, the use of clinical guidelines, and clinical practice patterns in the management of advanced PC in SEA. Most panelists (81%) voted prostate-specific antigen (PSA) as the most effective test for early PC diagnosis and risk stratification. Nearly 44% of panelists agreed that prostate-specific membrane antigen positron emission tomography-computed tomography imaging for PC diagnostic and staging information aids local and systemic therapy decisions. The majority of the panel preferred abiraterone acetate (67%) or docetaxel (44%) as first-line therapy for symptomatic mCRPC patients. Abiraterone acetate (50%) is preferred over docetaxel as a first-line treatment in metastatic castration-sensitive prostate cancer patients with high-volume disease. However, the panel did not support the use of abiraterone acetate in non-metastatic castration-resistant prostate cancer (nmCRPC) patients. Apalutamide (75%) is the preferred treatment option for patients with nmCRPC. The cost and availability of modern treatments and technologies are important factors influencing therapeutic decisions. All panelists supported the use of generic versions of approved therapies. The survey results reflect real-world management of advanced PC in a SEA country. These findings could be used to guide local clinical practices and highlight the financial challenges of modern healthcare.

Carbon Ion Radiation Therapy for Nonmetastatic Castration-Resistant Prostate Cancer: A Retrospective Analysis

PurposeTreatment outcomes of definitive photon radiotherapy for nonmetastatic castration-resistant prostate cancer (nmCRPC) are reportedly unsatisfactory. Carbon ion radiotherapy (CIRT) has shown favorable tumor control in various malignancies, including radioresistant tumors. Therefore, we retrospectively evaluated the clinical outcomes of CIRT for nmCRPC. Methods and MaterialsPatients with nmCRPC (N0M0) treated with CIRT at a total dose of 57.6 Gy (relative biological effectiveness; RBE) in 16 fractions or 51.6 Gy (RBE) in 12 fractions were included. The castration-resistant status was diagnosed based on prostate-specific antigen kinetics showing a monotonic increase during primary androgen deprivation therapy (ADT) or the need to change ADT. Clinical factors associated with patient prognosis were explored. Twenty-three consecutive patients were identified from our database. The median follow-up period was 63.6 months (range, 14.1–120). ResultsSeven patients developed biochemical relapse, six had clinical relapse, and four died from the disease. The 5-year overall survival, local control rate, biochemical relapse-free survival, and clinical relapse-free survival were 87.5%, 95.7%, 70.3%, and 75.7%, respectively. One patient with diabetes mellitus requiring insulin injections and taking antiplatelet and anticoagulant drugs developed grade 3 hematuria and bladder tamponade after CIRT. None of the patients developed grade 4 or worse toxicity. ConclusionsThe present findings indicate the acceptable safety and favorable efficacy of CIRT, encouraging further research on CIRT for nmCRPC.

Adverse events and costs among non-metastatic castration-resistant prostate cancer patients

Background Limited real-world evidence exists on the economic burden of adverse events (AEs) to the healthcare system among patients with non-metastatic castration-resistant prostate cancer (nmCRPC) treated with second-generation androgen receptor antagonists (ARAs). Current data is needed to understand real-world clinical event rates among ARAs and the cost of these events. Objectives Describe the incidence of non-central nervous system (CNS)-related AEs and CNS-related AEs among nmCRPC patients treated in the United States with second-generation ARAs (apalutamide and enzalutamide) and evaluate healthcare resource utilization (HCRU) and costs for these patients. Methods and study design This was a retrospective observational cohort study using claims data from Optum Clinformatics Data Mart to identify adult males with prostate cancer, castration, no metastases, and >1 claim for apalutamide or enzalutamide. The study was conducted from January 2017 to March 2020, with a patient index identification period from January 2018 to December 2019. AEs were classified as CNS-related or non-CNS-related. Results Of 605 patients (156 apalutamide and 449 enzalutamide), most were ≥65 years (94%) and had ≥1 non-CNS-related AE (55%). Many had ≥1 CNS-related AE (32%). Pain (12%) and arthralgia (11%) were the most frequently reported non-CNS-related AEs. Fatigue/asthenia (14%) and dizziness (7%) were the most frequently reported CNS-related AEs. Among patients with versus without non-CNS-related AEs, 34% versus 8% had emergency room (ER) events, and 25% versus 2% had inpatient events. Among patients with versus without CNS-related AEs, 41% versus 14% had ER events, and 38% versus 4% had inpatient events. Adjusted per-patient per-year cost (in 2020 USD) differences were significant between patients with and without non-CNS-related AEs ($30,765, p = 0.0018) and between patients with and without CNS-related AEs ($40,689, p = 0.0017). Conclusion There is significant HCRU and cost burden among nmCRPC patients treated with ARAs developing AEs, highlighting the need for treatments with improved tolerability. Additional studies are warranted to include recently approved agents.