Radium-223 dichloride (
Ra) is an α-emitter approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, but without visceral involvement. Despite being ...a life-prolonging therapy (LPT),
Ra remains underutilized. A large body of real-world evidence (RWE) for
Ra has been published in the decade since the pivotal phase 3 ALSYMPCA study, a period during which the treatment landscape has continued to evolve. How to optimize
Ra use, including how to integrate it into the mCRPC management pathway amongst other current LPTs (i.e., with respect to timing and concurrent, layered, or sequential use), is therefore of considerable interest. RWE studies lack the conventional restraints of clinical trials and can therefore help to build an understanding of how treatments may be best used in routine practice. Here we review RWE studies investigating the efficacy and safety of
Ra in mCRPC including in sequence with the recently approved 177-Lutetium conjugated to the ligand prostate-specific membrane antigen (
Lu-PSMA), as well as response marker development, imaging techniques, and current clinical practice recommendations.
TPS243
Background: DARO, a structurally distinct and highly potent androgen receptor inhibitor, has low blood–brain barrier (BBB) penetration and limited potential for drug–drug interactions. In ...phase 3 trials, DARO showed significant efficacy and a favorable safety profile. In ARAMIS (NCT02200614), DARO and androgen-deprivation therapy (ADT) significantly improved metastasis-free survival and overall survival (OS) vs placebo + ADT in pts with nonmetastatic castration-resistant prostate cancer. In ARASENS (NCT02799602), DARO + ADT + docetaxel significantly improved OS in pts with metastatic hormone-sensitive prostate cancer vs placebo + ADT + docetaxel. In both studies, the incidence of adverse events (AEs) was similar between treatment groups. Currently, the ARASTEP study (NCT05794906) is evaluating DARO and ADT in pts with high-risk BCR following primary therapy who have prostate-specific membrane antigen PET/CT-positive lesions. Based on a neuroimaging study of healthy volunteers, cerebral blood flow was not altered with DARO but was significantly reduced in brain areas related to cognition with ENZA. It is postulated that the low BBB penetration of DARO may result in lower serum testosterone elevations than those seen with ENZA, which may reduce the frequency of AEs. The ARAMON study (NCT05526248) will compare the effect of DARO and ENZA monotherapy on post-treatment testosterone levels in pts with CSPC who developed a BCR after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of pts with histologically or cytologically confirmed adenocarcinoma of the prostate who experienced BCR after radical primary prostatectomy (RP) or radiation therapy (RT), with <5 asymptomatic oligometastatic disease sites. Key inclusion criteria are prostate-specific antigen (PSA) ≥2 ng/mL, PSA doubling time of ≤20 months, serum testosterone >150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During the lead-in phase, 25 pts will receive DARO 600 mg twice daily for 52 weeks. If serum testosterone criteria are met at 12 weeks, the study will proceed to the randomized phase where approximately 40 pts will be randomized 1:1 to DARO (600 mg twice daily) or ENZA (160 mg once daily) for 52 weeks. The primary endpoint is the change in serum testosterone level from baseline to Week 12. Secondary endpoints include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of endocrine, glycemic, and lipid metabolism markers; incidence of AEs; and quality of life. As of September 2023, 23 of 25 planned pts in the lead-in phase have been enrolled. Clinical trial information: NCT05526248 .
For patients with metastatic hormone-sensitive prostate cancer, metastatic burden affects outcome. We examined efficacy and safety from the ARASENS trial for subgroups by disease volume and risk.
...Patients with metastatic hormone-sensitive prostate cancer were randomly assigned to darolutamide or placebo plus androgen-deprivation therapy and docetaxel. High-volume disease was defined as visceral metastases and/or ≥ 4 bone metastases with ≥ 1 beyond the vertebral column/pelvis. High-risk disease was defined as ≥ 2 risk factors: Gleason score ≥ 8, ≥ 3 bone lesions, and presence of measurable visceral metastases.
Of 1,305 patients, 1,005 (77%) had high-volume disease and 912 (70%) had high-risk disease. Darolutamide increased overall survival (OS) versus placebo in patients with high-volume (hazard ratio HR, 0.69; 95% CI, 0.57 to 0.82), high-risk (HR, 0.71; 95% CI, 0.58 to 0.86), and low-risk disease (HR, 0.62; 95% CI, 0.42 to 0.90), and in the smaller low-volume subgroup, the results were also suggestive of survival benefit (HR, 0.68; 95% CI, 0.41 to 1.13). Darolutamide improved clinically relevant secondary end points of time to castration-resistant prostate cancer and subsequent systemic antineoplastic therapy versus placebo in all disease volume and risk subgroups. Adverse events (AEs) were similar between treatment groups across subgroups. Grade 3 or 4 AEs occurred in 64.9% of darolutamide patients versus 64.2% of placebo patients in the high-volume subgroup and 70.1% versus 61.1% in the low-volume subgroup. Among the most common AEs, many were known toxicities related to docetaxel.
In patients with high-volume and high-risk/low-risk metastatic hormone-sensitive prostate cancer, treatment intensification with darolutamide, androgen-deprivation therapy, and docetaxel increased OS with a similar AE profile in the subgroups, consistent with the overall population.Media: see text.
TPS5111
Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor with low blood–brain barrier penetration. In the phase 3 ARAMIS study (NCT02200614) of ...patients with nonmetastatic castration-resistant prostate cancer, treatment with darolutamide significantly improved metastasis-free survival and overall survival versus placebo, with a favorable safety profile. The incidences of central nervous system adverse events (AEs; e.g. falls, memory impairment, and depression) showed a ≤2% difference between the darolutamide and placebo groups. Fatigue was the only AE with an incidence of > 10% for darolutamide (13.2% vs 8.3% for placebo). In a separate neuroimaging study of healthy volunteers, cerebral blood flow was not altered in patients treated with darolutamide but was significantly reduced in brain areas related to cognition in patients treated with enzalutamide. Furthermore, it is postulated that the low blood–brain barrier penetration of darolutamide may result in lower serum testosterone elevations than those seen with enzalutamide, with the potential of leading to fewer associated feminizing AEs. The objective of ARAMON (NCT05526248) is to compare the effect of darolutamide and enzalutamide monotherapy on post-treatment testosterone levels in patients with hormone-naive prostate cancer experiencing biochemical recurrence after definitive treatment for localized disease. Methods: ARAMON is a two-stage, open-label, phase 2 study of patients with histologically or cytologically confirmed adenocarcinoma of the prostate who have biochemical recurrence after radical primary prostatectomy or radiation therapy, with a prostate-specific antigen (PSA) doubling time of ≤20 months, baseline serum testosterone > 150 ng/dL, and Eastern Cooperative Oncology Group performance status 0/1. During a 52-week lead-in phase, 25 patients will receive darolutamide 600 mg twice daily. If criteria based on serum testosterone increase from baseline to Week 12 are met, the study will proceed to a 52-week randomized phase in which the effects of darolutamide (600 mg twice daily, n = 20) will be compared with the effects of enzalutamide (160 mg once daily, n = 20). The primary endpoint of both phases is the change in serum testosterone level from baseline to Week 12. Secondary endpoints of the randomized phase include the change in serum testosterone levels from baseline to Weeks 24 and 52; PSA at Weeks 4, 12, 24, 36, and 52; changes in blood levels of markers for glucose, lipid metabolism, and endocrine function related to sex hormones; safety; and quality of life. Safety will be assessed through AE monitoring. The first of the 25 planned patients in the lead-in phase was enrolled on January 13, 2023. Clinical trial information: NCT05526248 .
5022 Background: In pts with nmCRPC, metastatic progression was not consistently associated with PSA progression in a prior analysis of ARAMIS (Morgans AK, et al. J Clin Oncol 2022;40:5044). We ...evaluated prostate cancer (PC)-specific survival in ARAMIS, and the patterns of disease progression were determined overall and for pts who achieved PSA <0.2 ng/mL. Methods: Pts with nmCRPC received darolutamide (DARO n=955) or placebo (PBO n=554) + ADT in ARAMIS. Using the primary data cutoff (Sept 2018) excluding pts with baseline metastases, PC-specific survival accounting for other deaths as competing risk was analyzed. Treatment group–generated state sequence plots characterized pts by different events: radiological progression, PSA progression, or death. Based on PSA levels and conventional imaging q16 weeks during ARAMIS, the cumulative incidence of time to radiological progression was compared between pts with PSA <0.2 ng/mL and those without. In pts with PSA <0.2 ng/mL and who experienced radiological progression, we evaluated PSA levels at the time of radiological progression. Results: DARO increased overall survival in ARAMIS vs PBO (HR 0.69; 95% CI 0.53–0.88) and notably reduced PC-related deaths. PC was the leading cause of death in pts with nmCRPC in both treatment arms. Fewer pts receiving DARO vs PBO had PSA progression alone (7.8% vs 35.9%) or both PSA and radiological progression (5.4% vs 21.4%) at 12 months. Pts on DARO vs PBO had lower PSA levels at the time of radiological progression (median, 2.4 vs 3.7 ng/mL). DARO led to deep and durable PSA response vs PBO, with 25.1% vs 0.5% of pts achieving PSA <0.2 ng/mL, and DARO delayed time to PSA progression overall (median, 33.2 vs 7.3 months; HR 0.13; 95% CI 0.11–0.16). DARO pts with PSA <0.2 ng/mL had a lower risk of radiological progression vs those with PSA ≥0.2 ng/mL, with rates of 8.7% vs 33% at 24 months. At 36 months, the cumulative incidence of radiological progression remained at 8.7% for DARO pts with PSA <0.2 ng/mL and increased to 50% in pts with PSA ≥0.2 ng/mL. For the 11 pts with PSA <0.2 ng/mL and radiological progression, PSA levels at the time of radiological progression (range, 0.02–438.46 ng/mL) and time to radiological progression (4–22 months) did not follow any patterns. Conclusions: In pts with nmCRPC by conventional imaging, DARO increased overall survival vs PBO. Adding DARO to ADT resulted in deep and durable PSA response vs ADT alone. DARO was associated with low rates of PSA progression ± radiological progression. In DARO pts with PSA <0.2 ng/mL, the risk of radiological progression ± PSA progression was low over 24 months and did not increase through the end of the study. These post hoc results may raise questions about the frequency of conventional imaging for disease progression in pts with nmCRPC. Clinical trial information: NCT02200614 .
5083 Background: Darolutamide (DARO) is a structurally distinct and highly potent androgen receptor pathway inhibitor (ARPI). In ARASENS (NCT02799602), the addition of DARO to androgen-deprivation ...therapy (ADT) and docetaxel (DOC) significantly reduced the risk of death by 32.5% in patients (pts) with mHSPC, despite most placebo (PBO) pts (75.6%) receiving subsequent therapy. DARO also delayed time to progression to metastatic castration-resistant prostate cancer (mCRPC; median, not reached vs 19.1 months for PBO), resulting in a longer time in mHSPC, which is associated with improved quality of life vs mCRPC. We report post-progression subsequent anticancer therapies and related survival from ARASENS. Methods: Pts with mHSPC were randomized 1:1 to DARO 600 mg twice daily or PBO in addition to ADT + DOC. After treatment discontinuation, pts entered active and long-term survival follow-up periods during which assessments included subsequent therapies and survival outcomes. Post-progression survival was defined as time from first subsequent therapy to death using Kaplan-Meier estimates. Results: Of 1305 treated pts (DARO n=651; PBO n=654), 315 receiving DARO and 495 receiving PBO entered follow-up. Of these, 57% (n=179) and 76% (n=374), respectively, received subsequent therapy; abiraterone and enzalutamide were the most frequent first subsequent therapy (Table). In the DARO arm, 90% of first subsequent therapies were ARPI or chemotherapy. Minimal difference was observed in post-progression survival between subsequent therapies, suggesting subsequent therapy with another ARPI does not provide further survival benefit vs non-ARPI options (mainly chemotherapy). In contrast, in the PBO arm where the majority (78%) received first subsequent therapy with an ARPI, a survival benefit was observed vs non-ARPI subsequent therapies (median, 23.0 vs 13.5 months). Conclusions: DARO+ADT+DOC increased overall survival vs PBO+ADT+DOC and also delayed time to progression to mCRPC. DARO pts had similar survival with all post-progression therapies. Pts receiving PBO+ADT+DOC quickly progressed to mCRPC and treatment with an ARPI in ARPI-naïve pts improved survival. Clinical trial information: NCT02799602 . Table: see text
In patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the Androgen Receptor Antagonizing Agent for Metastasis-free Survival (ARAMIS) trial, darolutamide significantly ...improved median metastasis-free survival by nearly 2 years and reduced the risk of death by 31% versus placebo, with a favourable safety/tolerability profile. This post hoc analysis of ARAMIS evaluated efficacy and safety in patients by number of comorbidities and concomitant medications.
Patients with nmCRPC were randomised 2:1 to darolutamide (n = 955) or placebo (n = 554) while continuing androgen-deprivation therapy. Overall survival (OS) and treatment-emergent adverse events (TEAEs) were evaluated in subgroups by median numbers of ongoing comorbidities and concomitant medications. HRs were determined from univariate analysis using Cox regression.
Median numbers of comorbidities and concomitant medications were 6 and 10, respectively, with 41.6% of patients having >6 comorbidities and 48.8% taking >10 concomitant medications. For patients with ≤ 6 and >6 comorbidities, darolutamide increased OS versus placebo (hazard ratio HR 0.65 and 0.73, respectively), and this benefit was consistent for cardiovascular, metabolic, and other comorbidities (HR range: 0.39–0.88). For patients taking ≤ 10 and >10 concomitant medications, increased OS was also observed with darolutamide versus placebo (HR 0.76 and 0.66, respectively), and the benefit was consistent across medication classes (HR range: 0.45–0.80). Incidences of TEAEs and TEAEs leading to treatment discontinuation with darolutamide were similar to placebo across subgroups by numbers of comorbidities and concomitant medications.
The OS benefit and safety of darolutamide remained consistent with that observed in the overall ARAMIS population, even in patients with high numbers of comorbidities or concomitant medications.
NCT02200614.
Darolutamide increased overall survival versus placebo, and incidences of most adverse events were similar between treatments in patients with ≤ 6 or >6 comorbidities and those taking ≤ 10 or >10 concomitant medications.
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•Patients with nmCRPC in ARAMIS had a substantial comorbidity burden.•Darolutamide provided consistent survival benefit across comorbidity subgroups.•Darolutamide improved survival independent of the number of concomitant medications.•Safety of darolutamide in these subgroups was consistent with overall population.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
5050
Background:
223
Ra improved overall survival (OS) and quality of life and demonstrated a favorable safety profile in pts with mCRPC in the phase 3 ALSYMPCA trial. REASSURE (NCT02141438) is a ...global, prospective, single-arm, observational study of
223
Ra use in pts with mCRPC and bone metastases in routine clinical practice. Here, we present clinical outcomes from the second planned interim analysis of REASSURE for pts treated in the US. Methods: This analysis included pts with confirmed mCRPC with bone metastases scheduled to receive
223
Ra in the US. All pts received ≥1 dose of
223
Ra. Primary endpoints are short- and long-term safety, including incidence of bone marrow suppression and second primary malignancies (SPM). Secondary endpoints included OS and pt-reported pain (Brief Pain Inventory – Short Form BPI–SF scores). A clinically meaningful pain response was defined as a decrease from baseline of ≥2 points in BPI-SF worst pain item. Results: Pts were enrolled from 2014–2017. Overall, 498 pts were included in this analysis. At the data cut-off (20 March 2019), the median duration of observation was 11.9 months (0.4–41.3). Most pts (81%) had bone metastases only; 69% of pts received 5–6
223
Ra injections. Overall, 77% of pts had received ≥1 prior life-prolonging therapies: abiraterone (45%), enzalutamide (48%), docetaxel (25%), cabazitaxel (6%), or sipuleucel-T (24%). Concomitant enzalutamide was received by 31% of pts, and 47% received concomitant bone health agents. After
223
Ra, 31% of pts received ≥1 life prolonging therapies. During treatment, 208/358 (58%) pts with a baseline BPI-SF ≥2 had a clinically meaningful pain response. Any-grade and grade ≥3 drug-related treatment-emergent adverse events (TEAEs) occurred in 32% and 10% of pts, respectively. Drug-related TEAEs resulted in
223
Ra discontinuation in 4% of pts. Treatment-emergent and drug-related serious AEs (SAEs) occurred in 21% and 6% of pts, respectively. The most common (>5% of pts) any-grade drug-related TEAEs were diarrhea (10%), fatigue (9%), anemia (8%) and nausea (7%). Overall, 4% of pts had fractures; 2% of pts developed bone disorders. Eleven SPMs occurred in 10 pts (2%). In total, 60% of pts died during study follow-up. Median OS was 17.8 months (95% CI 15.6–19.4). Conclusions: Within the current treatment landscape in routine clinical practice in the US, median OS after
223
Ra treatment was close to 18 months. A majority of pts completed 5–6
223
Ra injections. The known safety profile of
223
Ra was confirmed with no new safety signals. Over half of pts with pain at baseline had a clinically meaningful pain response during
223
Ra treatment. Clinical trial information: NCT02141438 .
TPS5111
Background: Darolutamide is a structurally distinct and highly potent androgen receptor inhibitor (ARI) that significantly improved metastasis-free survival by ̃2 years and reduced the risk ...of death by 31% vs placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC). Darolutamide has a favorable safety and tolerability profile, with only ≤2% difference vs placebo for most adverse events (AEs) of interest (falls, fractures, hypertension, mental impairment). Fatigue was the only AE with > 10% incidence in the darolutamide arm (13.2%; placebo, 8.3%). Darolutamide has shown lower blood–brain barrier penetration than other ARIs in preclinical models (supported by human neuroimaging studies), which may lead to a lower risk of central nervous system-related AEs and has a low potential for drug–drug interactions. For patients with metastatic hormone-sensitive prostate cancer (mHSPC), the combination of darolutamide and ADT is expected to offer a favorable benefit–risk profile. ARASEC will evaluate the efficacy and safety of darolutamide plus ADT in mHSPC in the US (NCT05059236) and complement the data in the ongoing ARANOTE study (NCT04736199). Methods: ARASEC is a US-based, phase 2, open-label, single-arm study with an external control arm. Eligible patients will have confirmed adenocarcinoma of the prostate, radiologic evidence of metastatic disease by conventional imaging, and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Patients with mHSPC will receive darolutamide 600 mg twice daily plus ADT (luteinizing hormone-releasing hormone agonist/antagonist or orchiectomy). The control arm for ARASEC will be derived from the 393 patients with mHSPC treated with ADT alone in the CHAARTED trial. Patients in the active arm will be matched 1:1 to patients in the control arm using important baseline characteristics such as age, ECOG PS, extent of disease defined as low or high volume according to CHAARTED, and presence of bone and visceral metastases. Study duration was defined as the time from the first patient’s first visit until either the event count threshold triggering the primary endpoint analysis has been met or all patients have been followed for ≥2 years after enrollment, whichever occurs later. The primary endpoint is progression-free survival (PFS), defined in CHAARTED as the time from enrollment to prostate-specific antigen (PSA) progression, clinical progression (including radiological or symptomatic progression or clinical deterioration), or death, whichever occurs first. Secondary endpoints are overall survival, radiographic PFS, time to CRPC, complete PSA response rate at 6 months, and safety. Patient recruitment is in progress. Clinical trial information: NCT05059236.
