Adjuvant Aspirin for Stage III Colorectal Cancer after Curative Resection: Primary Analysis of the Randomized Double-blind Placebo-controlled Phase III Trial (EPISODE-III: JCOG1503C)

Presenter: Atsuo Takashima

Background

Observational evidence indicates that aspirin may confer a protective benefit in colorectal cancer (CRC); however, robust evidence in the adjuvant setting remains inconclusive. Phase III trials in unselected populations have not consistently demonstrated efficacy, whereas biomarker-driven studies suggest potential benefit in tumors harboring PI3K pathway alterations.

Aim

The EPISODE-III trial was designed to determine whether low-dose aspirin improves disease-free survival (DFS) in patients with unselected stage III CRC receiving standard adjuvant chemotherapy.

Methods

• EPISODE-III is a multicenter, randomized, double-blind, placebo-controlled phase III trial.
• Eligible patients aged 20–80 years with ECOG performance status 0–1 and histologically confirmed stage III CRC adenocarcinoma (cecum to upper rectum), who underwent curative (R0) resection with D2/D3 lymphadenectomy, were enrolled.

• A total of 882 patients were randomized (1:1) to receive either:

• Low-dose aspirin - 100 mg once daily (n= 440)
• Matching placebo (n=442)

• Both administered for 3 years alongside standard adjuvant chemotherapy (capecitabine, mFOLFOX6, or CAPOX).

• Endpoints
  • Primary endpoint: DFS
  • Secondary endpoints: Overall survival (OS), relapse-free survival (RFS), relative dose intensity (RDI), and safety
• The planned sample size (n=880) provided 80% power to detect a hazard ratio (HR) of 0.741 (one-sided α=0.05), assuming a 3-year DFS improvement from 74% to 80%.

Results

• Median follow-up: 4.0 years
• DFS events: 231 total (124 placebo; 107 aspirin)

Baseline characteristics were well-balanced:

• Median age: 65 vs. 64 years
• Stage distribution (IIIA/IIIB/IIIC): ~19% / 62–63% / 18–19%
• Oxaliplatin-based therapy: ~70–71%

Table 1 : 3 yr Efficacy Outcomes

Endpoint	Placebo (%)	Aspirin (%)	HR	P-value (one-sided)
DFS	75.4	78.8	0.84	0.0987
RFS	77.2	79.5	0.87	–
OS	96.6	95.2	1.02	–

 

• Three-year DFS was 75.4% with placebo versus 78.8% with aspirin (+3.4%), but the primary endpoint was not achieved (HR 0.84, 95% CI 0.65–1.09; one-sided p=0.0987).

• RFS showed a similar non-significant trend.
• OS was comparable between the two arms.

Safety and Treatment Exposure

• Grade ≥3 adverse events were comparable between arms
• Aspirin-related grade ≥3 toxicity was  <1%
• Lower gastrointestinal bleeding occurred in 4 patients
• One treatment-related death occurred in the aspirin arm (ischemic heart disease during chemotherapy)
• Median relative dose intensity: 98.6% in both groups, indicating excellent adherence

Conclusion

The addition of low-dose aspirin to standard adjuvant chemotherapy did not result in a statistically significant improvement in DFS in an unselected stage III CRC population. Nonetheless, a modest numerical benefit in DFS, coupled with favorable tolerability and high treatment adherence, was observed.

BREAKWATER: Progression-free and Overall Survival Analyses of First-line (1L) Encorafenib + Cetuximab (EC) + FOLFIRI in BRAF V600E-mutant Metastatic Colorectal Cancer (mCRC).

Presenter: Scott Kopetz

Background

Leucovorin/5-fluorouracil combined with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) constitutes standard 1L therapy for metastatic colorectal cancer (mCRC). In patients with BRAF V600E-mutant mCRC, phase III BREAKWATER study demonstrated significant improvements in ORR, PFS, and OS with encorafenib plus cetuximab and mFOLFOX6 (EC+mFOLFOX6) vs chemotherapy ± bevacizumab. A safety lead-in phase indicated that EC+FOLFIRI was tolerable with promising efficacy.

Aim

BREAKWATER Cohort 3 was subsequently conducted to evaluate EC+FOLFIRI and updated PFS, OS, and safety outcomes are reported.

Methods

• Cohort 3 enrolled patients with previously untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0–1.
• Patients(n=147) were randomized (1:1) to receive EC+FOLFIRI (n=73) or standard control therapy (FOLFIRI ± bevacizumab) (n=74).

• Primary endpoint: ORR by blinded independent central review (BICR)
• Key secondary endpoint: PFS by BICR
• Other secondary endpoints: OS and safety

Results

• Median follow-up
• PFS: 18.0 vs 14.4 months
• OS: 20.6 vs 20.7 months
• Median treatment duration:
• EC+FOLFIRI: 67.9 weeks
• Control: 32.1 weeks

Efficacy Outcomes

• EC+FOLFIRI significantly improved PFS, meeting the key secondary endpoint.
• A clinically meaningful OS prolongation was observed.
• Previously reported ORR was significantly higher with EC+FOLFIRI (64.4% vs 39.2%).

Endpoint	EC+FOLFIRI	Control	HR(95% CI); p value
mPFS (mo)	15.2 (13.6, NE)	8.3 (6.9, 9.8)	HR 0.44 (0.27–0.70); p=0.0002
mOS (mo)	NE (21.0, NE)	20.3 (13.2, NE)	HR 0.56 (0.34–0.94)
18-mo OS (%)	72.0	54.5	—

NE, not estimable

Safety Outcomes

• Safety profile was manageable and consistent with known toxicities.

• No new safety signals were identified.

Safety Parameter	EC+FOLFIRI (%)	Control (%)
Serious TEAEs	49	44
Grade 3/4 TEAEs	70	81
Discontinuation due to AEs	14	10

Conclusion

• BREAKWATER Cohort 3 demonstrated that EC+FOLFIRI provides significant improvements in ORR and PFS, along with prolonged OS, in patients with BRAF V600E-mutant mCRC.
• The regimen exhibited a manageable safety profile without new toxicities.

These findings support EC+FOLFIRI as an additional practice-changing 1L treatment option, enabling more individualized, patient-centered therapeutic strategies.

Adjuvant Sintilimab-Capecitabine versus Capecitabine Alone in Locoregionally Advanced Nasopharyngeal Carcinoma with Suboptimal Response to Induction Chemotherapy: An Open-Label, Randomized, Controlled, Phase 2 Trial.

Presenter: Li-Ting Liu

Background

Induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) is standard for locoregionally advanced nasopharyngeal carcinoma (LA-NPC). However, patients who respond poorly to IC remain at high risk of progression. While adjuvant capecitabine improves outcomes in high-risk cases, the added benefit of combining it with the PD-1 inhibitor sintilimab is uncertain.

Aim

To determine whether adding sintilimab to adjuvant capecitabine improves PFS in LA-NPC patients with a suboptimal response to IC.

Methods

• Design: Open-label, randomized phase 2 trial
• Participants: 150 patients (18–70 years) with stage II–IVA LA-NPC and suboptimal IC response
• Intervention:
• Experimental: Sintilimab + capecitabine
• Control: Capecitabine alone
• Treatment schedule: Both groups received 8 cycles; sintilimab was given intravenously alongside capecitabine
• Primary endpoint: 2-year PFS (intention-to-treat)
• Safety Outcomes: Assessed in all treated patients

Results

• 2-year PFS:
• Sintilimab + capecitabine: 88.2%
• Capecitabine alone: 87.8%
• No significant difference (HR 0.85; p=0.77)
• Adverse events:
• Grade 3–4: 34% (combination) vs 31% (control)
• Most common: Hand-foot syndrome
• Immune-related myocarditis (grade 3): 3% in combination group
• No treatment-related deaths

Conclusion

Adding sintilimab to capecitabine did not significantly improve PFS in high-risk LA-NPC patients after IC. Future research should focus on biomarker-guided patient selection and optimizing immunotherapy use.

Ultra-Low-Dose Immunotherapy Plus Oral Metronomic Chemotherapy versus Paclitaxel-Carboplatin in Platinum-Sensitive Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Randomized Phase III Trial

Presenter: Minit Shah

Background

Platinum-based chemotherapy (PBC) combined with pembrolizumab or cetuximab is the standard 1L treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC), but access is limited in many resource-constrained settings. Triple oral metronomic chemotherapy combined with ultra-low-dose immunotherapy (TMC-I) has shown promising efficacy and tolerability in earlier studies.

Aim

To compare the efficacy and safety of TMC-I versus paclitaxel–carboplatin (PBC) as 1L palliative therapy in patients with R/M-HNSCC.

Methods

• Design: Open-label, multicenter, randomized phase III trial
• Participants: 422 patients with R/M-HNSCC
• Intervention:
• Arm A: Paclitaxel + carboplatin every 3 weeks
• Arm B: TMC-I (oral methotrexate, celecoxib, erlotinib + nivolumab every 3 weeks)
• Endpoints:
• Primary: Overall survival (OS)
• Secondary: PFS, ORR, safety, quality of life (QoL)
• Follow-up: Median ~11 months

Results

OS:

• 12-month OS: 46% (TMC-I) vs 23% (PBC)
• Median OS: 10.3 vs 6.2 months (HR 0.565; p < 0.001)

PFS :

• Median PFS: 5.5 vs 2.7 months (HR 0.465; p < 0.001)

Response rate:

• ORR: 53.4% vs 24.1% (p < 0.001)

Safety and QoL:

• Grade ≥3 adverse events: 34.1% vs 46.4% (p = 0.010)
• No treatment-related deaths
• QoL preserved in TMC-I arm

Conclusion

TMC-I significantly improves survival, response rates, and tolerability compared to standard PBC, while maintaining quality of life. It represents a cost-effective and practical 1L treatment option for R/M-HNSCC, especially in resource-limited settings.

Event-free Survival with Adjuvant Selpercatinib in Stage IB-IIIA RET Fusion-positive NSCLC: Primary Results of the Phase 3 LIBRETTO-432 Trial

Presenter: Jonathan Goldman

Background

Selpercatinib is a selective, brain-penetrant RET inhibitor approved for advanced RET fusion-positive (RET+) non-small cell lung cancer (NSCLC). However, its role in early-stage (IB–IIIA) RET+ NSCLC, where recurrence risk remains high and no adjuvant targeted therapy is established, has not been previously studied.

Aim

To evaluate the efficacy and safety of adjuvant selpercatinib compared with placebo in patients with stage IB–IIIA RET+ NSCLC following definitive locoregional treatment.

Methods

• Design: Phase 3, randomized, double-blind, placebo-controlled trial (LIBRETTO-432)
• Participants: 151 patients with stage IB–IIIA RET+ NSCLC
• Intervention:

• Selpercatinib 160 mg twice daily for up to 3 years
• Placebo (with crossover allowed upon recurrence)

• Endpoints:
• Primary: Investigator-assessed event-free survival (EFS) in stage II–IIIA patients
• Secondary: EFS in overall population, blinded independent central review (BICR) EFS, OS, and safety
• Follow-up: Median ~24–27 months

Results

• Event-free survival (stage II–IIIA):
• HR 0.172 (p=0.0003), significantly favoring selpercatinib
• Median EFS: Not reached vs 31.8 months (placebo)
• 2-year EFS: 91.5% vs 61.1%
• Independent review (BICR):
• Consistent benefit (HR 0.125; p=0.0011)
• Overall population:
• HR 0.165 (p=0.0002), strongly favoring selpercatinib
• Safety:
• Adverse events consistent with known profile (common: increased ALT/AST)
• No treatment-related deaths
• All deaths (n=3) occurred in placebo arm due to disease

Conclusion

Adjuvant selpercatinib significantly improves event-free survival in early-stage RET+ NSCLC with a manageable safety profile. These findings support the use of targeted therapy in the adjuvant setting and highlight the importance of genomic testing at diagnosis to guide treatment decisions.

Perioperative (Neoadjuvant and Adjuvant) Apalutamide (APA) + Androgen Deprivation Therapy (ADT) vs Placebo (PBO) + ADT with Radical Prostatectomy (RP) in High-Risk Localized or Locally Advanced Prostate Cancer (HR LPC/LAPC): Final Analysis of the PROTEUS Phase 3 Study.

Presenter: Mary-Ellen Taplin

Background

High rates of relapse have been reported in patients with high-risk localized or locally advanced prostate cancer (HR LPC/LAPC) despite radical prostatectomy (RP).

Aim

To evaluate whether apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT before and after RP with pelvic lymph node dissection will improve pathologic complete response/minimal residual disease (pCR/MRD) and metastasis-free survival (MFS) in HR LPC/LAPC

Methods

• Patients with newly diagnosed HR LPC/LAPC were randomized 1:1 to blinded APA (240 mg/d) or PBO as neoadjuvant treatment (tx) for 6 mo + ADT, with a 2-wk break prior to and a 4-wk break post RP, followed by 6 mo of assigned tx
• Primary end points: pCR/MRD (≤ypT2, ≤5 mm tumor diameter) and MFS
• Secondary end points: EFS, time to first subsequent tx (TTST1), time to distant metastasis (TTDM), and safety
• Exploratory end points: residual cancer burden (RCB/MRD; ≤ypT2, ≤0.25 cm³) and investigator-assessed MFS

Results

• 2109 patients (median age of 66 years; PSA, 14.8 ng/mL; GS ≥8, 95.8%)
• Patients were randomized to APA + ADT [n=1057] or PBO + ADT [n=1052]
• Median follow-up: 61.7 mo

• Efficacy:
  • APA + ADT achieved the primary end points vs PBO + ADT: pCR/MRD rate was significantly higher (8.9% vs 1.0%; odds ratio [OR] 10.17; p<0.0001); MFS by BICR significantly improved (HR 0.80; p=0.0169) and 5-y MFS rate of 78.2% vs 73.5%
  • APA + ADT improved investigator-assessed MFS (HR 0.74; nominal p=0.0004)
  • APA + ADT significantly improved EFS, TTST1, TTDM (Table) and RCB/MRD: MRD (30.6% vs 11.7%; OR 3.36; nominal p<0.0001)
• Safety:
  • Grade 3/4 tx-emergent adverse events (TEAEs) for APA + ADT vs PBO + ADT were 39.6% vs 31.0%, respectively
  • Discontinuation due to TEAEs for APA + ADT vs PBO + ADT were 7.4% vs 2.7%, respectively

Conclusions

• APA + ADT significantly increased the curative success of RP in patients with HR LPC/LAPC, with a 10-fold higher odds of pCR/MRD and a clinically meaningful 20% reduction in risk of distant metastasis or death
• APA + ADT also improved the secondary end points
• Combined APA + ADT and RP may emerge as a new standard of care for patients with HR LPC/LAPC

	HR	p Valuea	APA + ADT n=1057 Median (mo)	PBO + ADT n=1052 Median (mo)
EFS	0.71	<0.0001	57.1	38.4
TTST1 (local, regional, or systemic, including ADT reinitiation)	0.65	<0.0001	74.2	41.5
TTDM (conventional or PSMA PET imaging)	0.68	0.0002	NR	NR

^aStratified by GS (7, ≥8), nodal status, and geographic region (North America, European Union, rest of world).

Ivonescimab plus Chemotherapy versus Tislelizumab plus Chemotherapy in Previously Untreated Advanced Squamous Non–Small Cell Lung Cancer: Overall Survival Results of the Phase 3 HARMONi-6 Trial.

Presenter: Chen Zhiwei

Background

In the prespecified interim analysis of PFS from the HARMONi-6 study, ivonescimab combined with chemotherapy significantly improved PFS compared with tislelizumab plus chemotherapy in patients with previously untreated advanced squamous NSCLC (sq-NSCLC).

Aim

To evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy on prespecified OS in patients with advanced squamous NSCLC

Methods

• Patients with previously untreated stage III-IV sq-NSCLC
• Randomly assigned (1:1) to receive ivonescimab 20 mg/kg or tislelizumab 200 mg every 3 weeks (Q3W), each in combination with paclitaxel (175 mg/m²) and carboplatin (AUC 5) for 4 cycles, followed by maintenance ivonescimab or tislelizumab monotherapy
• Randomization was stratified by disease stage (IIIB/IIIC versus IV) and PD-L1 tumor proportion score (TPS; ≥1% versus <1%)
• Primary endpoint: PFS
• Secondary endpoint: OS
• This was the first planned OS analysis with an efficacy boundary of one-sided P=0.0049

Results

• Patients: 532; randomly assigned (n=266 per arm)
• Median follow-up: 21.4 months
• Efficacy:
  • Ivonescimab plus chemotherapy significantly improved OS compared with tislelizumab plus chemotherapy (median OS 27.9 months versus 23.7 months; hazard ratio [HR], 0.66; one-sided P=0.0017)
  • The OS benefit was consistent across prespecified subgroups
  • Among patients with PD-L1 TPS <1%, median OS was NE versus 18.6 months (HR, 0.64)
  • Among patients with PD-L1 TPS≥1%, median OS was NE versus 27.3 months (HR, 0.68)
• Safety:
  • Safety profile of ivonescimab plus chemotherapy was consistent with earlier studies and no new safety concerns were noted

Conclusions

• Ivonescimab plus chemotherapy significantly improved OS compared with tislelizumab plus chemotherapy in previously untreated patients with advanced sq-NSCLC
• Ivonescimab plus chemotherapy emerged as the first regimen to show clinical superiority over an active PD-1 inhibitor control arm in the first-line setting
• The dual-targeted approach of ivonescimab established a compelling new standard of care in the management of advanced sq-NSCLC

Daraxonrasib, a RAS(ON) Multi-Selective Inhibitor vs Chemotherapy in Previously Treated Metastatic Pancreatic Adenocarcinoma (mPDAC): Primary and Final Analysis from the Phase 3 RASolute 302 Study.

Presenter: Brian Wolpin

Background

Available second-line (2L) therapies offer limited clinical benefit in mPDAC with reported mPFS of 3-4 mo and mOS of 6-7 mo. Aberrant RAS pathway activation with oncogenic RAS mutations (mut) were identified in >90% of cases, most commonly at codon G12. Daraxonrasib is an oral, RAS(ON) multi-selective, tri-complex inhibitor of the active, GTP-bound state of mutant and wild type RAS.

Aim

To evaluate the efficacy and safety of daraxonrasib in patients with 2L mPDAC and ECOG performance status (PS) 0-1

Methods

• RASolute 302, a global, randomized, open-label, phase 3 study was conducted in patients with 2L mPDAC and ECOG PS 0-1
• Patients were randomized 1:1 to receive daraxonrasib 300 mg PO QD or investigator’s choice of SOC cytotoxic chemo
• Dual primary endpoints: OS and PFS by BICR in the RAS G12 mutant (RAS G12) population
• Secondary endpoints: OS and PFS by BICR in the overall population, ORR by BICR in RAS G12 and overall populations

Results

• 248 patients were randomized to daraxonrasib and 252 to chemo
• Median follow-up: 8.5 months
• Efficacy:
  • Statistically significant, clinically meaningful improvements in OS and PFS were observed with daraxonrasib vs chemo in the RAS G12 and overall populations (Table)
• Safety:
  • Gr ≥3 TRAEs (treatment-related adverse events) occurred in 43.6% of patients receiving daraxonrasib vs 57.5% receiving chemo
  • The most common (≥10%) Gr ≥3 TRAEs were rash (13.7%) and stomatitis (12.0%) for daraxonrasib; neutrophil decrease (18.2%) and anemia (16.4%) for chemo
  • TRSAEs occurred in 10.8% of patients receiving daraxonrasib vs 18.7% receiving chemo
  • Discontinuation due to TRAEs occurred in 1.2% of patients for daraxonrasib vs 11.2% for chemo
  • Median/mean daraxonrasib dose intensity was 93.1%/84.7%

Conclusions

• Daraxonrasib improved OS and PFS vs chemo in patients with 2L mPDAC with or without an identified tumor RAS mut
• Daraxonrasib was generally well tolerated, with no new safety concerns
• Daraxonrasib may emerge as the new SOC for 2L mPDAC

 

		RAS G12		Overallb
		Daraxonrasib n=228	Chemo n=231	Daraxonrasib n=248	Chemo n=252
OS	Median; mos	13.2	6.6	13.2	6.7
	HR P-value	0.40 <0.0001		0.40 <0.0001
PFSa	Median; mos	7.3	3.5	7.2	3.6
	HR P-value	0.45 <0.0001		0.49 <0.0001
ORRa	%	33.2	11.8	31.6	11.2

^aBy BICR.

^bRAS G12, G13 or Q61 mut or no RAS mut identified.

Palbociclib Plus Tamoxifen ± Goserelin in Women with Hormone Receptor (HR)-Positive, HER2-Negative Advanced Breast Cancer (BC): PATHWAY, an Asian International Double-Blind Randomized Phase 3 Trial—Final Overall Survival (OS) Analysis.

Presenter: Yen-Shen Lu

Background

The incidence of breast cancer (BC) is increasing in Asia, and peaks before menopause; tamoxifen is commonly used for pre/perimenopausal BC. Nevertheless, tamoxifen is not approved for use in combination with CDK4/6 inhibitors in many countries. The primary analysis of PATHWAY study showed significant improvement in PFS with palbociclib plus tamoxifen (± goserelin) with immature OS.

Aim

To evaluate the PFS and final OS at the end of the study.

Methods

Study Design: A phase 3 study conducted in Japan, Korea, Taiwan, and Singapore.

Patient Population: Women with locally advanced or metastatic HR-positive, HER2-negative BC eligible for 1st- or 2nd-line tamoxifen-based endocrine therapy and without a prior exposure to CDK4/6 inhibitor.

Treatment: 1:1 randomization (as stratified by line of therapy and menopausal status) as follows:

Group 1: Palbociclib (125 mg daily, days 1–21 of a 28-day cycle)

Group 2: Placebo

Both groups received tamoxifen 20 mg daily, pre/perimenopausal patients additionally received goserelin.

Endpoints: PFS (primary endpoint) and final OS

Results

Enrolment: 184 patients (pre/perimenopausal: 28.3%, postmenopausal: 71.7%), 60.9% received study treatment as 1st-line and 39.1% as 2nd-line endocrine therapy.

Primary endpoint: PFS- 154 events

Deaths: 105

Significant improvement in updated PFS with palbociclib plus tamoxifen vs. placebo plus tamoxifen (HR 0.594; 95% CI, 0.427–0.825; P < 0.001), median PFS (24.4 vs. 11.1 months).

PFS benefit observed irrespective of menopausal status (pre/perimenopausal: HR 0.343; 95% CI, 0.175–0.675; postmenopausal: HR 0.697; 95% CI, 0.479–1.012).

Final OS in favor of palbociclib plus tamoxifen (HR 0.772; 95% CI, 0.525–1.134; P = 0.093), median OS (71.7 vs. 62.0 months).

OS benefits consistent across menopausal subgroups (pre/perimenopausal: HR 0.747; 95% CI, 0.339–1.647; postmenopausal: HR 0.772; 95% CI, 0.497–1.198).

Palbociclib plus tamoxifen was generally well tolerated, with manageable adverse events.

Conclusions

Palbociclib plus tamoxifen (± goserelin) provided durable PFS benefit and a favorable OS trend and a manageable safety profile during a longer follow-up. The findings support the regimen as an effective option in BC patients, regardless of menopausal status.

Subgroup Analyses by Disease Volume and de novo/Recurrent mHSPC in the PSMAddition Study of [¹⁷⁷Lu]Lu-PSMA-617

Presenter: Fred Saad

Background

The at rPFS interim analysis of the phase 3 PSMAddition study demonstrated that combining [¹⁷⁷Lu]Lu-PSMA-617 (¹⁷⁷Lu-PSMA-617) with ADT + ARPI significantly improved rPFS in patients with PSMA+ mHSPC vs ADT + ARPI (HR: 0.72; 95% CI 0.58, 0.90; p = 0.002).

Aim

To evaluate the impact of ¹⁷⁷Lu-PSMA-617 across various subgroups of patients with PSMA+ mHSPC

Methods

Patient Population: Patients with treatment-naive/minimally treated mHSPC diagnosed by CT/MRI/bone scan and ≥1 PSMA+ metastatic lesion on [⁶⁸Ga]Ga-PSMA-11 PET/CT.

Treatment: 1:1 randomization to ¹⁷⁷Lu-PSMA-617 (7.4 GBq ± 10% q6w, 6 cycles) + ADT + ARPI (¹⁷⁷Lu-PSMA-617 arm) or ADT + ARPI (control arm).

Endpoints: Primary Endpoint: rPFS (centrally assessed rPD per PCWG3/RECIST v1.1 or death)

Selected Secondary efficacy, safety, and patient-reported outcomes (PROs) assessed in subgroups of high/low disease volume (DV) per CHAARTED criteria (locally assessed by CT/MRI/bone scan; prespecified) and de novo/recurrent mHSPC (AJCC stage ≥/<IVb; post hoc).

Results

Enrolment: 1144 patients (¹⁷⁷Lu-PSMA-617 arm; n=572, control arm; n= 572).

High DV: 68.0% vs. 68.2%, de novo mHSPC: 52.1% vs. 47.9%.

Efficacy and PRO HRs were generally similar for the ¹⁷⁷Lu-PSMA-617 arm vs control arm in the overall population and DV and mHSPC subgroups (Table).

Table: Efficacy and PRO outcomes

HR (95% CI) for177Lu-PSMA-617 arm vs control arm	Overall N = 1144	High DV n = 779	Low DV n = 365	De novomHSPC n = 572	Recurrent mHSPC n = 523
rPFSa	0.72 (0.58, 0.90)	0.72 (0.56, 0.92)	0.73 (0.42, 1.27)	0.74 (0.54, 1.01)	0.74 (0.53, 1.04)
PFS per investigatorb	0.64 (0.51, 0.79)	0.61 (0.48, 0.78)	0.80 (0.46, 1.37)	0.65 (0.48, 0.88)	0.64 (0.46, 0.89)
Time to:
PSA progression	0.42 (0.30, 0.59)	0.43 (0.31, 0.62)	0.29 (0.08, 1.05)	0.51 (0.32, 0.79)	0.35 (0.21, 0.60)
Symptomatic skeletal event	0.89 (0.62, 1.26)	0.93 (0.64, 1.37)	0.67 (0.27, 1.66)	0.97 (0.60, 1.57)	0.82 (0.48, 1.40)
mCRPC	0.70 (0.58, 0.84)	0.67 (0.54, 0.82)	0.87 (0.55, 1.37)	0.61 (0.47, 0.80)	0.75 (0.56, 1.00)
BPI-SF pain intensity worseningc	1.02 (0.87, 1.18)	0.98 (0.82, 1.18)	1.09 (0.83, 1.44)	1.06 (0.85, 1.31)	0.97 (0.78, 1.22)
FACT-P total score worseningc	1.14 (0.98, 1.33)	1.13 (0.94, 1.37)	1.16 (0.88, 1.53)	1.13 (0.90, 1.41)	1.16 (0.92, 1.46)
EQ-5D-5L worseningc	1.13 (0.97, 1.31)	1.04 (0.87, 1.25)	1.34 (1.01, 1.77)	1.17 (0.93, 1.45)	1.09 (0.87, 1.37)

N may differ across outcomes.

^arPD by BIRC or death.

^bComposite of radiographic, clinical, and PSA progression and death.

^cComposite with clinical progression and death.

Incidences of AEs, grade ≥3 AEs, serious AEs, and selected safety topics of interest (cytopenias, dry mouth) were similar across subgroups within each treatment arm.

Conclusions

Combining ¹⁷⁷Lu-PSMA-617 with ADT + ARPI improved rPFS vs ADT + ARPI in patients with PSMA+ mHSPC. The benefits were evident subgroups of patients with high/low DV and de novo/recurrent mHSPC. Other efficacy outcomes, PROs, and the safety profile were generally consistent across subgroups.

Reference: Annual Meeting of the American Society of Clinical Oncology (ASCO 2026), 29^th May – 6^th June 2026, Chicago, IL.