ERLEADA - Use of ERLEADA with Concurrent Radiotherapy

SUMMARY

• In the phase 3 TITAN study (NCT02489318) that evaluated ERLEADA compared to placebo in patients with metastatic castration-sensitive prostate cancer (mCSPC) receiving continuous androgen deprivation therapy (ADT), patients were excluded if radiation therapy (RT) was administered within 28 days of randomization. Additionally, concomitant RT for new painful metastatic prostate cancer lesions that were not present on baseline imaging was prohibited. Efficacy and safety analyses were not performed for patients who received palliative radiation to lesions at baseline in the TITAN study.^1,2
• In the phase 3 SPARTAN study (NCT01946204) that evaluated the efficacy and safety of ERLEADA compared to placebo in patients with high-risk, non-metastatic castration-resistant prostate cancer (nmCRPC) receiving continuous ADT, patients were permitted to receive salvage radiation for locoregional pelvic disease to treat localized progression or symptoms while continuing treatment with ERLEADA.^3,4 Two patients (0.2%) and 1 patient (0.3%) in the ERLEADA and placebo groups, respectively, received concomitant RT. Efficacy and safety analyses were not performed for patients who received concomitant RT in the SPARTAN study.⁵
• Other phase 3 studies are also evaluating concomitant use of ERLEADA with RT; however, efficacy and safety results have not been published.
  • ATLAS (NCT02531516): ongoing study evaluating addition of ERLEADA to gonadotropin-releasing hormone agonist (GnRHa) and external beam radiation therapy (EBRT) in patients with high-risk localized or locally advanced prostate cancer.^6-8
  • PRIMORDIUM (NCT04557059): ongoing study evaluating addition of ERLEADA to RT and a luteinizing hormone-releasing hormone agonist (LHRHa) in patients with high-risk, prostate-specific membrane antigen-positron emission tomography (PSMA-PET)-positive hormone-sensitive prostate cancer (HSPC).^9,10
• FORMULA-509 (NCT03141671) is an ongoing, phase 2, randomized, open-label, multicenter study evaluated the efficacy and safety outcomes of adding 6 months of ERLEADA plus abiraterone acetate with prednisone (AAP) or 50 mg bicalutamide to the standard of care (SOC) regimen of 6 months of GnRHa with salvage RT in patients with high-risk features and a detectable progression-free survival (PSA) following radical prostatectomy (RP; N=345). Patients received salvage RT plus 6 months of GnRHa and were randomized to receive concurrent ERLEADA 240 mg once daily (QD) plus abiraterone acetate 1000 mg plus prednisone 5 mg or bicalutamide 50 mg.¹¹
  • In the ERLEADA plus AAP group vs bicalutamide group, the 3-year PFS rate was 74.9% vs 68.5% (hazard ratio [HR], 0.71; 90% confidence interval [CI], 0.49-1.03). Among patients with baseline PSA >0.5 ng/mL, the 3-year PFS rate was 67.2% vs 46.8% (HR, 0.50; 95% CI, 0.27-0.95).
  • Adverse events (AEs) were generally consistent with expected safety profiles. The most common grade ≥2 AEs were maculopapular rash, hypertension, and diarrhea.
• Early results from an ongoing phase 2 study in patients with metachronous oligometastatic HSPC treated with ERLEADA plus ADT and stereotactic body radiation therapy (SBRT; N=180)¹² and an ongoing phase 2 study in patients with very high-risk, node negative prostate cancer treated with ERLEADA plus AAP plus leuprolide and ultra-hypofractionated radiation (UHRT; N=63)¹³ have been reported.
• Additional results from smaller (<50 patients) phase 2 studies have been published.
  • STARTAR (NCT03311555): evaluated the combined treatment of ERLEADA and ADT for 9 months with EBRT followed by 6 cycles of adjuvant docetaxel compared to the historical controls from the STREAM study in patients with PSA-recurrent prostate cancer after RP.¹⁴
  • MetaCURE (NCT03436654): evaluated SBRT with ERLEADA plus ADT with vs without AAP to osseous lesions in patients with newly diagnosed, histologically confirmed prostate cancer.¹⁵
  • SATURN (NCT03902951): evaluated addition of ERLEADA, AAP, and PSMAPET/computed tomography (CT)-guided metastasis-directed SBRT to intermittent ADT for patients with oligorecurrent metastatic hormone‑sensitive prostate cancer (mHSPC) after prior RP.¹⁶
  • SOLAR (NCT03298087): evaluated combination of radical local (RP with lymph node dissection and postoperative RT or radical RT directed to the prostate, seminal vesicles, and pelvic lymph nodes) metastasis-directed SBRT, and intensified systemic therapies of limited duration (6 months on leuprolide, AAP, and ERLEADA) in patients with de novo oligometastatic prostate cancer.¹⁷
  • Phase 2 study: evaluated ERLEADA plus ADT and radiobiologically dose-escalated ultra-hypofractionated prostate and pelvic SBRT in very high-risk patients.¹⁸
• The study descriptions of ongoing phase 3 studies^19-21 and ongoing phase 2 study²² in patients treated with ERLEADA and concurrent RT, results from a phase 2 study that evaluated salvage RT with vs without ERLEADA in biomarker-stratified patients with transcriptionally defined molecular subtypes of recurrent prostate cancer,²³ and results from real-world studies evaluating the impact of prostate RT in patients with mHSPC receiving ERLEADA^24-26 have been published.

Clinical Data

Phase 3 Studies

TITAN Study

Chi et al (2019)¹ evaluated the efficacy and safety of ERLEADA plus ADT compared to placebo plus ADT in patients with mCSPC (N=1052). Patients were randomized 1:1 to receive either ERLEADA 240 mg orally (PO) QD (n=525) or placebo QD (n=527). All patients in the TITAN study received a concomitant GnRH analog or had a bilateral orchiectomy (NCT02489318).

Patients were excluded if RT was administered within 28 days of randomization. Concomitant RT for new painful metastatic prostate cancer lesions that were not present on baseline imaging was prohibited. Additionally, patients discontinued ERLEADA treatment due to clinical progression, which included the need to initiate RT due to tumor progression (even in the absence of radiograph evidence of disease). Palliative radiation to lesions existing at baseline was not considered clinical progression.²

Efficacy and safety analyses were not performed for patients who received palliative radiation to lesions at baseline in the TITAN study.

SPARTAN Study

Smith et al (2018)³ study evaluated the efficacy and safety of ERLEADA in patients with nmCRPC (N=1207). Patients were randomized 2:1 to receive either ERLEADA 240 mg PO QD (n=806) or placebo QD (n=401). All patients in the SPARTAN study received a concomitant GnRH analog or had a bilateral orchiectomy. Salvage radiation for locoregional pelvic disease to treat localized progression or symptoms was permitted while continuing treatment with ERLEADA (NCT01946204).⁴

Patient baseline demographic and disease characteristics were well balanced, and there were no significant differences between groups. The median treatment duration was 16.9 months in the ERLEADA group and 11.2 months in the placebo group.^3,5 Shown below is Table: Frequency of Concomitant Radiotherapy in the SPARTAN Study.

Efficacy and safety analyses were not performed for patients who received concomitant RT in the SPARTAN study.

Additional Information

Additional information regarding the SPARTAN study from the clinical study report can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/rev_210951_arn-509-003_CSR_Redacted.pdf.

ATLAS Study

ATLAS is an ongoing study evaluating the efficacy and safety of adding ERLEADA to GnRHa and EBRT in patients with high-risk localized or locally advanced prostate cancer.^6-8

Study Design/Methods

• Phase 3, randomized, double-blind, placebo-controlled, multicenter study
• A total of 1503 patients were randomized 1:1 to receive the following treatments during each 28-day treatment cycle:
  • Cycles 1-2 (neoadjuvant to RT)
    • Group 1: ERLEADA 240 mg QD, bicalutamide placebo, and GnRHa
    • Group 2: placebo, bicalutamide, and GnRHa
  • Cycles 3-4 (concurrent with RT)
    • Group 1: RT with ERLEADA 240 mg QD, bicalutamide placebo, and GnRHa
    • Group 2: RT with placebo, bicalutamide, and GnRHa
  • Cycles 5-30 (adjuvant to RT)
    • Group 1: ERLEADA 240 mg QD and GnRHa
    • Group 2: placebo and GnRHa
• Select inclusion criteria: indicated and planned to receive primary RT for prostate cancer; histologically confirmed adenocarcinoma of an intact prostate and either GS ≥8 and ≥clinical stage T2c (≥cT2c) or Gleason score (GS) ≥7, PSA ≥20 ng/mL and ≥cT2c; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; Charlson Comorbidity Index (CCI) ≤3; and adequate liver function
• Select exclusion criteria: presence of distant metastasis and history of pelvic radiation; prior treatment with GnRH analog, antiandrogen, or both for >3 months prior to randomization; prior procedural or systemic treatment for prostate cancer; cytochrome P450 17 (CYP17) inhibitors, radiopharmaceutical agents, immunotherapy, or any investigational agent; prior treatment with systemic glucocorticoids ≤4 weeks prior to randomization or is expected to require long-term use of corticosteroids during the study; and history of seizure
• Primary endpoint: Metastasis-free survival (MFS)
• Key secondary endpoints: event-free survival (EFS), time to PSA progression, and overall survival (OS)
• Other secondary endpoints: time to next local or systemic treatment, time to distant metastasis, and MFS by conventional or positron emission tomography (PET) imaging

Results

Patient Characteristics

• Efficacy and safety results have not been published; however, patient baseline characteristics are available.
  • A total of 90% of patients received standard EBRT to the prostate/pelvis over 68 weeks, while 10% and 6% of patients received hypofractionation and EBRT combined with brachytherapy, respectively.⁸
  • Patient retention and physician engagement strategies were initiated during the coronavirus disease 2019 (COVID-19) pandemic, and a 96% patient retention rate was observed.²⁷

PRIMORDIUM Study

PRIMORDIUM is an ongoing study evaluating the efficacy and safety of adding ERLEADA to RT and a LHRHa compared to RT and a LHRHa alone in high-risk patients with PSMA-PET-positive HSPC. Patients who are PSMA-PET-negative at baseline will be enrolled into the observational cohort.^9,10

Study Design/Methods

• Phase 3, randomized, open-label, multicenter, global study
• A total of ~412 PSMA-PET-positive patients to achieve ~192 events and ~200 PSMA-PET-negative patients will be included in the interventional and observational cohorts, respectively. This study is not designed to compare results across cohorts.
• The treatments in the interventional cohort are randomized 1:1 as described in the Table: Treatments in the Interventional Cohort.
• Patients who are PSMA-PET-negative and enrolled in the observational cohort will receive SOC treatment per local practice and will have data collected during routine clinical practice which will include therapies administered, clinical evaluations, disease progression assessments, and survival until closure of the interventional cohort.

Treatments in the Interventional Cohort^9,10,a

• Patients in the interventional cohort will be stratified by location of PSMA-PET-positive lesions, PSA doubling-time (PSADT), and planned use of SBRT.
  • At sites where it is a standard approach, SBRT may be used for ≤3 prostate-specific membrane antigen (PSMA)-avid distant metastases; the decision to use SBRT must be made before randomization.
• In the interventional cohort, PSA will be measured every 3 months until the primary endpoint. If the PSA remains <0.2 ng/mL, PSMA-PET is assessed by blinded independent central review (BICR) at 6 and 12 months, then annually until PSMA-PET progression. If PSA rises to ≥0.2 ng/mL, PSMA-PET is done immediately then every 6 months until PSMA-PET progression. Testosterone and PROs will additionally be assessed.
  • Post-PSMA-PET-progression assessments will include bone scans, CT/magnetic resonance imaging (MRI), and patient-reported outcomes (PROs).
• Select inclusion criteria: histologically confirmed adenocarcinoma of the prostate; previously treated with RP with or without lymph node dissection and either any postoperative PSA of <0.1 ng/mL within 12 months after RP and without any PSA ≥0.1 ng/mL within the 4- to 8-week period after RP for biochemical recurrence (BCR) after RP or PSA ≥0.1 ng/mL within the 4- to 8-week period after RP for persistent PSA after RP, confirmed by additional measurement ≥3 weeks later; biochemically recurrent prostate cancer after RP with high risk of developing metastasis defined as pathological GS ≥8 or PSADT ≤12 months; no evidence of metastases on screening CT/MRI of the chest/abdomen/pelvis, and technetium-99m (^99mTc) whole-body bone scan; ECOG PS 0 or 1; results of PSMA-PET at screening as determined by BICR had to be:
  • PSMA-PET-negative for any prostate cancer lesions (ie, no locoregional lesion and no distant lesions)
  • PSMA-PET-positive for ≥1 locoregional (pelvic) lesion without distant extra pelvic lesion
  • PSMA-PET-positive for ≥1 locoregional (pelvic) lesion with extra pelvic lesion(s)
• Select exclusion criteria: history of pelvic radiation for malignancy; history of ADT or chemotherapy for prostate cancer; prior treatment for BCR; prior treatment with a CYP17 inhibitor, androgen receptor antagonist, medication that lowers androgen levels, or bilateral orchiectomy; small cell or neuroendocrine carcinoma of the prostate; clinically significant cardiovascular disease; use of 5-alpha-reductase inhibitor or an investigational agent ≤4 weeks prior to randomization; history of seizure or at increased risk of seizure
• Primary endpoint: PSMA-PET metastatic progression-free survival (ppMPFS), defined as the appearance of at least 1 new PSMA-PET-positive distant lesion compared with the previous scan assessed by BICR, or death
• Secondary endpoints: time to PSA progression; PSA response rate; PSA levels at end of week 26; time to locoregional progression by PSMA-PET; OS; prostate cancer-specific survival; and AEs

Results

• Efficacy and safety results have not been published.
• Baseline characteristics of patients enrolled in both cohorts through the data cutoff date of January 12, 2023 have been published.²⁸

Phase 2 Studies

FORMULA-509 Study

Nguyen et al (2026)¹¹ evaluated the efficacy and safety outcomes of adding 6 months of ERLEADA plus AAP or 50 mg bicalutamide to the SOC regimen of 6 months of GnRHa with salvage RT in patients with high-risk features and a detectable PSA following RP (N=345).

Study Design/Methods

• Phase 2, randomized, open-label, multicenter study
• Patients received salvage RT plus 6 months of GnRHa and randomization was to concurrent ERLEADA 240 mg QD plus abiraterone acetate 1000 mg plus prednisone 5 mg or bicalutamide 50 mg. Radiation to pelvic nodes was required for pN1 and was optional for pN0.
• Patients were stratified by PSA at study entry (>0.5 vs ≤0.5 ng/mL) and pN0 vs pN1.
• Select inclusion criteria: PSA ≥0.1 ng/mL following RP and ≥1 high-risk feature, including GS 8-10, postoperative PSA >0.5 ng/mL, pT3, PSADT <10 months, negative surgical margins, persistent PSA after RP, local recurrence visible on imaging, or a high-risk score (>0.6) on the Decipher RP test
• Primary endpoint: PSA PFS
• Secondary endpoint: MFS, determined by conventional imaging

Results

Patient Characteristics

• Twenty-nine percent of patients were pN1 and 31% of patients had PSA>0.5 ng/mL.

Efficacy

• Results are summarized in Table: Primary and Secondary Endpoint Results.
• The median follow-up was 34 months (interquartile range [IQR], 29-42).
• In a pre-planned analysis by stratification factors, the ERLEADA plus AAP group was superior to the bicalutamide group for PSA >0.5 for PFS (3-year PFS rate, 67.2% vs 46.8%; HR, 0.50; 95% CI, 0.27-0.95; 2-sided log-rank P-value=0.030) and MFS (3-year MFS rate, 84.3% vs 66.1%; HR, 0.32; 95% CI, 0.13-0.84; 2-sided log-rank P-value=0.014).

Health-related quality of life (HRQoL) Outcomes

• Patient-reported HRQoL was also evaluated using validated questionnaires at baseline, end of treatment, and 1 year after treatment. Both treatment arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change, -15 bicalutamide group, -15 ERLEADA plus AAP group) and increases in PROMIS Fatigue (median change, 6 bicalutamide group, 7.4 ERLEADA plus AAP group) from baseline to end of treatment, which improved to near baseline at 1 year after treatment for both groups.²⁹
• Median Saint Louis University Mental Status Exam (SLUMS) score was within normal range at baseline, end of treatment, and 1 year after treatment for both groups.²⁹
• There was no significant difference in patient-reported hormonal function, fatigue, or mental status between groups at end of treatment and 1 year after treatment.²⁹

Safety

• AEs were consistent with the known safety profiles of each medication, with higher rates of rash and hypertension reported in the ERLEADA plus AAP group.
• Specifically, grade ≥2 AEs of interest in the ERLEADA plus AAP group vs bicalutamide group included maculopapular rash (11.5% vs 0.6%), hypertension (22% vs 13%), diarrhea (8.5% vs 4.8%), cardiac disorders (3.0% vs 5.5%), and fatigue (7.9% vs 6.1%). In the ERLEADA plus AAP group, 3 patients withdrew because of AEs.

STARTAR Study

STARTAR¹⁴ was a phase 2 study that evaluated combined treatment of ERLEADA and ADT for 9 months with EBRT followed by 6 cycles of adjuvant docetaxel compared to the historical controls from the STREAM study in patients with PSA-recurrent prostate cancer after RP (N=39).

Study Design/Methods

• Phase 2, prospective, multicenter, single-arm, open-label study
• Patients received ADT for over 9 months and ERLEADA 240 mg orally daily for approximately 36 weeks.
• Beginning at week 8, EBRT at 64.8-68 Gy was administered to the prostate bed over 68 weeks, followed by a 4-week washout and then docetaxel 75 mg/m² intravenously every 3 weeks for up to 6 cycles.
• Primary endpoint: 36-month PSA PFS
• Secondary endpoints: proportion of patients at 12, 24, and 36 months with PSA levels of <0.1 ng/mL and testosterone recovery to >100 ng/dL, biochemical (PSA) PFS over time, PSA nadir, time to testosterone recovery, safety, and percentage of patients completing all treatments

Results

Baseline Characteristics

• The median age in the overall population and the STREAM cohort (N=38) was 64 years (IQR, 60-67 and IQR, 59-69, respectively).
• The median baseline PSA in the overall population and the STREAM cohort was 0.58 ng/mL (IQR, 0.35-1.06) and 0.4 ng/mL (0.29-0.75), respectively.
• All the patients in the STARTAR cohort completed the planned radiation treatment course. A higher rate of patients with N1 disease (6/9 [67%] with N1, 5/28 [18%] with N0, and none with Nx) underwent pelvic radiation.

Efficacy

• The median follow-up time for patients without progression was 37 months (IQR, 36-38).
• All patients who were evaluable for the primary endpoint were alive at the time of analysis, and all the patients (100%) achieved undetectable PSA as PSA nadir on treatment.
• The 2- and 3-year PFS were 84% and 71%, respectively; this improved significantly over the 3-year PFS of 47% in the historic control in the multimodality trial and 54% in the STREAM treatment cohort (P=0.004 and P=0.039, respectively).
• Testosterone recovery was reported in 4 (11%), 31 (82%), and all 37 patients at 1 year, 2 years, and data lock, respectively.
• PSA of <0.1 ng/mL with testosterone recovery was reported in 38%, 67%, and 69% of patients at 1, 2, and 3 years, respectively.
• The median time to testosterone recovery was 15 months (95% CI, 13-17).

Safety

• The most common AEs (>30%) included hot flashes (97%), fatigue (87%), alopecia (77%), anemia (59%), dysgeusia (59%), maculopapular rash (54%), diarrhea (44%), urinary frequency (44%), nausea (41%), insomnia (38%), urinary urgency (36%), paresthesia (36%), dyspnea (33%), pruritus (31%), and edema (31%).
• The maximum hematologic grade 3-4 AEs were neutropenia (27 [69%]), including 3 febrile neutropenia events during chemotherapy.
• Serious AEs observed included febrile neutropenia (3 [8%]) and 1 (2.6%) each of flu-like symptoms/sinus tachycardia, fever, pelvic infection, hematoma, and thromboembolism.
• Among patients who dose reduced or discontinued any part of study treatments, ERLEADA was held or dose reduced for 10 (25%) patients, with 2 (5%) patients discontinuing, and radiation was held for 1 (3%) patient.

MetaCURE Study

McHugh et al (2025)¹⁵ reported results from cohort B (n=33) in patients with newly diagnosed, histologically confirmed prostate cancer.

Study Design/Methods

• Phase 2, open-label, randomized, multicenter, multiarm study
• Cohort B evaluated SBRT with ERLEADA plus ADT with vs without AAP to osseous lesions.
  • Patients in cohort B were randomized to receive osseous lesion–directed SBRT at 4 months with either 10 months of ERLEADA plus ADT plus AAP or ERLEADA plus ADT.
• Inclusion criteria: retroperitoneal extrapelvic lymph nodes up to the level of the renal hilum with or without pelvic node spread (M1a) and/or low-volume bone metastases treatable within a maximum of 3 RT plans, and testosterone level ≥150 ng/mL
• Primary endpoint: Composite of pathologic complete response (pCR) or minimal residual disease (MRD; ≤5 mm of morphologically identifiable carcinoma) in the RP specimen
• Secondary endpoints: PSA <0.1 ng/mL with testosterone recovery at 24 months from initiation of systemic therapy and time to testosterone recovery (≥150 ng/dL) after discontinuation of ADT

Results

Efficacy

• pCR and/or MRD was achieved in 15% (5/33) of the patients (90% CI, 6-29). After RP, 9% (3/33; 90% CI, 3-22) vs 18% (6/33; 90% CI, 8-33) achieved pCR and/or MRD with ERLEADA plus ADT plus AAP vs ERLEADA plus ADT.
• Among patients with pCR/MRD, 5/5 patients had an undetectable PSA at 24 months with testosterone recovery.
• Testosterone recovery at 24 months from treatment initiation occurred in 6 (38%) vs 7 (41%) patients with ERLEADA plus ADT plus AAP vs ERLEADA plus ADT.
• A total of 3 (9%) patients did not undergo RP due to disease progression. One (3%) patient initiated a new systemic therapy at a follow-up duration of 18 months , and 1 (3%) patient continued treatment beyond the 10-month period per investigator discretion.
• At 18 months, 3 vs 1 patients had disease progression with ERLEADA plus ADT plus AAP vs ERLEADA plus ADT.
• At 24 months, 3 vs 3 patients had disease progression with ERLEADA plus ADT plus AAP vs ERLEADA plus ADT.

Safety

• No new safety signals were observed.

SATURN, a prospective, phase 2, single-arm, single-center study, evaluated the efficacy and safety of adding ERLEADA, AAP, and PSMA-PET/CT-guided metastasis-directed SBRT to intermittent ADT for patients with oligorecurrent mHSPC after prior RP (N=28). At 6 months after testosterone recovery (≥150 ng/dL following androgen annihilation therapy [AAT]), PSA was maintained at <0.05 ng/mL in 13 of 26 (50%) evaluable patients (95% CI, 32-67). The rates of grade 2 and 3 AAT toxicity were 21% each.¹⁶

SOLAR, a prospective, phase 2, single-arm study, evaluated the efficacy and safety of combining radical local (RP with lymph node dissection and postoperative RT or radical RT directed to the prostate, seminal vesicles, and pelvic lymph nodes) metastasis-directed SBRT, and intensified systemic therapies of limited duration (6 months on leuprolide, AAP, and ERLEADA) in veterans with de novo oligometastatic prostate cancer (N=28). At a median follow-up of 30 months among 22 evaluable patients, 19 (86%) were progression-free. Grade 2 and 3 toxicities, respectively, were reported in 46% and 4% of patients on primary tumor therapy; no patients on SBRT; and 42% and 4% of patients on systemic therapy. There was 1 grade 4 toxicity event.¹⁷

A post hoc analysis of the SOLAR and SATURN studies comparing oncologic outcomes in PSMA-PET-defined synchronous and metachronous oligometastatic castration‑sensitive prostate cancer (omCSPC) following systemic and tumor-directed interventions has also been published.³⁰

Francolini et al (2026)¹² reported early results of a phase 2 study in patients with metachronous oligometastatic HSPC treated with ERLEADA plus ADT and SBRT (N=180).

Study Design/Methods

• Phase 2, randomized study
• Patients were randomized into 2 groups:
  • Arm A (Control): SOC with ERLEADA plus ADT
  • Arm B (Treatment): ERLEADA plus ADT with SBRT on all sites of metastatic disease
• Exclusion criteria: patients with de novo metastatic disease or with >5 distant metastases
• Primary endpoint: complete biochemical response (CBR), defined as PSA <0.2 ng/mL, and predictive features of CBR at 6 months after treatment initiation in this population^12,31

Results

Efficacy

• Of the patients enrolled thus far, 154/180 reached a minimum follow-up of 6 months.
• In the overall population, 93.5% of patients achieved a CBR.
• Neither the presence of PSMA-positive lesions undetected on conventional imaging nor the presence of bone metastatic lesions affected the CBR rate (odds ratio [OR], 0.33; P=0.13 and OR, 1.22; P=0.77).
• Patients with <3 metastatic lesions had a significantly improved CBR rate (OR, 0.11; 95% CI, 0.03-0.44; P=0.002).

Safety

• Safety results were not reported.

McBride et al (2026)¹³ reported interim results of an ongoing phase 2 study in very high-risk patients with node negative prostate cancer treated with ERLEADA plus AAP plus leuprolide in conjunction with UHRT (N=63).¹³ 

Study Design/Methods

• Phase 2, open-label, single-arm, multi-institutional study
• Patients received treatment for 6 months with ERLEADA in combination with¹³:
  • AAP plus
  • Leuprolide and UHRT 7.5-8 Gy x 5 fractions
• Select inclusion criteria: very high-risk prostate cancer, defined as GS 8-10, PSA ≥20 ng/mL, clinical or radiographic ≥T3, any GS 9-10 disease, or >4 scores of GS 8 disease
• Select exclusion criteria: evidence of grossly involved lymph nodes on CT or MRI (>1.5 cm in short axis) or an International Prostate Symptom Score (IPSS) >20³²
• Primary endpoint: 3-year BCR rate by Phoenix criteria, with a prespecified superiority threshold of <10%, defined as an increase in post-treatment nadir PSA by ≥2 ng/mL¹³
• Secondary endpoint: proportion of patients who showed recurrence, based on the surgical definition of BCR (any post-treatment PSA ≥0.2 ng/mL), MFS, time to testosterone recovery >150 ng/dL, and OS

Results

Patient Characteristics (N=64)

• The median age was 69 years (range, 63-73), and the baseline serum PSA was 12 ng/mL (IQR, 7-28).
• A total of 45 (70%) patients had a GS of 9-10, 14 (22%) patients had a GS 8, and 5 (7.8%) patients had a GS 6-7.
• At diagnosis, the radiographic T stages (MRI) were as follows: T2, 16/64  (35%); T3a, 33/64 (39%); T3b, 12/64 (26%).

Efficacy (N=63)

• Phoenix-defined BCR was reported in 12 (19.0%) of 63 patients within 36 months after treatment, all of whom had testosterone normalization at the time of BCR.
• At a median follow-up of 41 months (range, 34-43), the Phoenix-defined biochemical relapse-free survival (bRFS) rate was 84.2% (95% CI, 75.6-93.7).
• Among the 63 evaluable patients, 37 (58%) patients experienced PSA recurrence >0.2 ng/mL using the surgical definition of BCR (any post-treatment PSA ≥0.2 ng/mL).
• The surgically defined 3-year bRFS was 42% (95% CI, 31.5-56.1).
• Four patients developed distant metastasis during follow-up, and the 3-year MFS was 93.6% (95% CI, 87.8-99.8).
• Among the 51 evaluable patients without Phoenix-defined BCR, 50 (98%) had normalized testosterone (>150 ng/dL) at last follow-up; the median PSA at that time was 0.10 ng/mL (IQR <0.05-0.20), and 36 patients (71%) had PSA <0.2 ng/mL.
• Among the 58 patients who achieved an undetectable PSA of <0.05 ng/mL during treatment, 8 had Phoenix-defined BCFs within 3 years of post-treatment follow-up.
  • The 3-year bRFS was 87.7% (95% CI, 79.5-96.7)
  • Undetectable PSA was reported in 4 of 6 patients (P=0.0025)

Safety (N=64)

• No acute (≤3 months of treatment completion) grade 4 treatment-related adverse events (TRAEs) were observed. Acute grade 3 TRAEs were reported in 17/64 patients (hypertension, n=12 [19%]; rash, n=3 [4.7%]; hyperglycemia, n=1 [1.6%], and diarrhea, n=1 [1.6%]).
• No grade 3/4 late (>3 months of treatment completion) TRAEs were reported. Grade 2 TRAEs (reproductive system and breast disorders) were reported in 1 (1.6%) patient.
• Statistically significant changes in the EPIC hormonal and sexual domains were observed at 12 months vs baseline (n=60), and in the EPIC sexual domain at 24 months vs baseline (n=46). No statistically significant changes were observed in the bowel and urinary domains from baseline to 12 months.

Dubinsky et al (2025)¹⁸ reported preliminary safety results from a phase 2 study in very high-risk patients treated with ERLEADA plus ADT and radiobiologically dose-escalated ultra-hypofractionated prostate and pelvic SBRT (N=20).

Study Design/Methods

• Phase 2, interventional clinical study
• Patients received treatment for 18 months with ERLEADA 240 mg QD in combination with ADT plus UHRT to the pelvic nodes (25 Gy), involved nodes (35 Gy), and prostate (36.25 Gy) x 5 fractions on alternate days during month 3.
• Patients were assigned to either localized or locally advanced high-risk category.
• Select inclusion criteria: European Association of Urology (EAU) high-risk localized or locally advanced prostate cancer with ECOG PS 0-1 and modified Charlson comorbidity index of ≤4. Staging was based on digital rectal examination and conventional imaging with mandatory pelvic multiparametric MRI and optional 68Ga PSMA-PET/CT
• Primary endpoint: 5-year biochemical control rate, safety
• Secondary endpoint: PROs

Results

Patient Characteristics

• The mean age was 65 years (range, 47-74), and the mean PSA was 26.9 ng/mL (IQR, 7.5-84.2).
• Overall, 65% of patients had International Society of Urological Pathology (ISUP) grade 4 or 5.
• At diagnosis, radiographic T stages (CT) were as follows: T3/4, 50%; N1, 25%.

Efficacy

Efficacy results were not reported.

Safety

• All patients were irradiated as planned and remained on ADT and ERLEADA, except 1 patient who underwent dose reduction of ERLEADA to 180 mg.
• Grades 1 and 2 acute gastrointestinal toxicity was observed in 50% and 25% of patients, respectively.
• Grades 1 and 2 acute genitourinary toxicity was observed in 40% and 20% of patients, respectively.
• No grade 3 toxicity was observed.
• AEs of special interest included grade 3 fall in 1 patient; grade 2 and 3 hypertension in 1 patient; grade 2 transitory ischemic attack in 1 patient; grade 1 and 2 skin rash in 2 and 1 patients, respectively; and grade 1 hypothyroidism in 1 patient.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 23 February 2026.