JCOG1019: An Open-label, Non-inferiority, Randomised Phase III Study Comparing the Effectiveness of Watchful Waiting (WW) and Intravesical Bacillus Calmette-Guérin (BCG) in Patients (Pts) with High-grade pT1 (HGT1) Bladder Cancer with pT0 on the Second Transurethral Resection (TUR) Specimen

Background

Intravesical BCG is the standard of care (SOC) for HGT1 bladder cancer. However, whether intravesical BCG is necessary for pts with HGT1 bladder cancer with pT0 histology on the 2nd TUR specimen remains unclear.

Aim

This study aimed to confirm the non-inferiority of WW to intravesical BCG in pts with HGT1 bladder cancer with pT0 on the 2nd TUR.

Methods

JCOG1019 is an open label, randomised, phase 3 study that included pts who underwent complete eradication of all visible bladder tumours using TUR and had a histopathological diagnosis of HGT1 bladder cancer.

After the 1st registration, pts underwent the 2nd TUR and were enrolled in the 2nd registration if the specimens showed pT0.

These pts were randomised in a 1:1 ratio to undergo WW or receive intravesical BCG for 8 weeks.

The primary endpoint was relapse-free survival (RFS), excluding the Tis and Ta intravesical recurrences.

Non-inferiority was shown if the upper limit of the two-sided 90% confidence interval (CI) of the hazard ratio (HR) was <1.60. Select secondary endpoints included overall survival (OS) and safety.

Results

• 513 pts were enrolled at the 1st registration.
• A total of 263 pts were enrolled in the 2nd registration and randomised (BCG: 133; WW: 130); patient characteristics were balanced between the arms. At the data cutoff, the median follow-up was 7.02 years.
• WW was non-inferior to BCG with respect to RFS (HR 0.692 [90% CI: 0.443-1.082 (<1.60)]; one-sided p=0.001 for non-inferiority by a stratified Cox regression).
• OS was similar (HR 0.640 [95% CI: 0.334-1.228]) in both the groups.
• Pts treated with BCG had a higher incidence of adverse events during the entire period, including follow-up, than those who underwent WW (90.2% vs. 50.0% in all grades; 3.8% vs. 3.1% in grade ≥3).

Conclusions

For pts with bladder cancer with HGT1 at the initial TUR and pT0 at the 2nd TUR, WW was non-inferior to intravesical BCG in terms of RFS, excluding Tis and Ta intravesical recurrences. The safety profile of WW was better than that of BCG. These results support WW as a new SOC for pts with HGT1 bladder cancer and no residual tumour at the 2nd TUR.

Reference

Annals of Oncology (2024) 35 (suppl_2): S1135-S1169. 10.1016/annonc/annonc1616

Nivolumab Plus Chemoradiotherapy in Patients with Non-metastatic Muscle-invasive Bladder Cancer (nmMIBC), Not Undergoing Cystectomy: A Phase II, Randomized Study by the Hellenic GU Cancer Group

Background

Trimodality therapy (TMT) consisting of maximal effort transurethral resection of Bladder Tumor (TURB-T) plus Chemoradiotherapy (CRT) is an effective alternative for patients with nmMIBC who cannot undergo or refuse radical cystectomy (RC).

Aim

The purpose of this study was to investigate the effect of concurrent nivolumab in addition to chemoradiotherapy in patients with non-metastatic MIBC who did not undergo RC

Methods

Eligible patients with nmMIBC staged cT2–T4a N0 M0 disease who previously underwent optimal TURB-T were randomized to receive nivolumab at 240 mg every 2 weeks concurrently to CRT (1st dose 14 days prior to radiotherapy initiation) followed by 6 cycles of nivolumab at 480mg every 4 weeks or to CRT (cisplatin concurrently with radical radiotherapy) alone.

Dose escalated radiotherapy to 66-70 Gy (2 Gy per fraction) was delivered in both arms. 2-year locoregional/distant relapse-free survival rate (RFSR) was the primary end point.

This is the first report of efficacy and toxicity after a median follow up of 17.7 months (95% CI 14.5-20.8).

Results

• Between June 2019 and October 2022, 72 patients entered the study: 35 were randomized to CRT alone arm (Arm 1) and 37 to nivolumab plus CRT (Arm 2).
• During follow up 16 patients relapsed in arm 1 and 9 in arm 2. 2-year RFSR in Arm 1 was 37.6% (18-57.1) vs. 59.9% (30.7-80.1) in arm 2 (p =. 040).
• Median overall survival was 24 months (95% CI 15.1-NR) for arm 1, while it was not reached for arm 2.
• Anemia and thyroid dysfunction were more frequent adverse events in arm 2 compared to arm 1.
• Grade ≥ 3 adverse events were reported in 24 (31.2%) patients: 10 (25.6%) in arm 1 and 14 (36.8%) in arm 2. There were no treatment-related deaths

Conclusion

The addition of nivolumab to TMT produced a significant increase in RFSR without any new safety signals being observed. These results warrant the conduction of a randomized phase III trial to establish nivolumab plus CRT as a new standard for patients with nmMIBC not undergoing RC.

Reference

Annals of Oncology (2024) 35 (suppl_2): S1135-S1169. 10.1016/annonc/annonc1616

Efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC Following Progression on an Androgen-receptor Pathway Inhibitor (ARPI) (SPLASH).

Background

Metastatic castration-resistant prostate cancer (mCRPC) is a fatal condition with a substantial unmet need. 177Lu-PNT2002 is a beta-emitting radioisotope chelated to a small-molecule ligand targeting PSMA.

Aim

To evaluate efficacy of 177Lu-PNT2002 in PSMA-positive mCRPC following progression on an ARPI.

Method

SPLASH is an open label phase 3 trial which enrolled PSMA PET-positive patients (pts) with mCRPC who progressed on one ARPI and have not received chemotherapy for castration resistant disease.

Pts were randomized 2:1 to either 177Lu-PNT2002 (6.8 GBq IV q8w up to 4 cycles) or alternate ARPI.

The primary endpoint was radiographic progression-free survival (rPFS) assessed by blinded independent central review (BICR) using RECIST 1.1/PCWG3.

Additional key endpoints included overall survival (OS), objective response rate (ORR), PSA50, HRQoL and safety. Crossover from alternate ARPI to 177Lu-PNT2002 was allowed after disease progression confirmed by BICR..

Results

• Of 488 pts screened with PSMA PET, 90.4% were PSMA positive; 412 were randomized to 177Lu-PNT2002 (n=276, median 4 cycles) or alternate ARPI (n=136).
• Demographics and baseline characteristics were well balanced between 177Lu-PNT2002 and ARPI: ECOG status 0: 58.7% vs. 55.9%; M0 status: 10.1% vs. 11.0%, respectively.
• Crossover rate was 84.6% (77/91). rPFS primary endpoint (mos, (95% CI)) was improved in pts receiving 177Lu-PNT2002 (9.5, (7.4, 10.0)) compared to ARPI (6.0, (4.7, 7.9)) (HR (95% CI): 0.71 (0.55, 0.92), p=0.0088).
• Other efficacy outcomes are provided in the table. Incidence of TEAEs leading to treatment discontinuation and grade ≥3 TEAEs were both lower with 177Lu-PNT2002 vs. ARPI ((5/269) 1.9% vs. (8/130) 6.2% and 30.1% vs. 36.9%, respectively).
• Most common TEAEs of 177Lu-PNT2002 were fatigue (53.5%), dry mouth (37.2%) and nausea (31.2%).

	177Lu-PNT2002	ARPI	HR (95% CI)
Median OS, mos (1st interim analysis)*	20.8 (19.1, NE)	NE (NE, NE)	1.11 (0.73, 1.69) p=0.6154
OS HR crossover adjusted:
IPCW**			0.72 (0.48, 1.12)
Two-Stage: recensoring**			0.85 (0.53, 1.36)
Two-Stage: no recensoring**			0.68 (0.44, 1.04)
ORR by BICR, % (n)***	38.1% (37/97)	12.0% (6/50)	p=0.0021
Median duration of response, mos	9.4 (5.9, 13.2)	7.3 (1.6, NE)
PSA50 response, % (n)***	35.7% (96/269)	14.6% (19/130)	p=0.0001
FACT-P total score, median time to deterioration, mos	8.1 (8.0, NE)	5.3 (4.4, 5.9)	0.59 (0.44, 0.80) p=0.0005
*assumes proportional hazards **exploratory OS crossover adjusted methods ***unconfirmed

 

Conclusions

177Lu-PNT2002 was well tolerated and improved rPFS, ORR, PSA50 and HRQoL in patients with PSMA-positive mCRPC in the pre-chemotherapy setting compared to alternative ARPI.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623.

Decipher mRNA Score for Prediction of Survival Benefit from Docetaxel at Start of Androgen Deprivation Therapy (ADT) for Advanced Prostate Cancer (PC): An Ancillary Study of the STAMPEDE Docetaxel Trials

Background

Docetaxel (Doce) is effective for metastatic (M1) PC but its effect is heterogeneous. Combining Doce with hormone therapy can improve overall survival (OS) but may not be appropriate for all.

Aim

This study hypothesised that the Decipher 22-gene mRNA score (DS) predicts Doce benefit.

Methods

DS were generated from whole transcriptome profiling with a clinical test (Veracyte) on tumor index cores from patients (pts) randomised 1:1 to ADT or ADT + Doce +/- zoledronic acid (ZA) in the STAMPEDE protocol (Oct 2005 - Mar 2013).

We followed a pre-defined statistical analysis plan to fit Cox models individually in M1 and very high-risk non-metastatic (M0) pts dichotomised by DS ( 0.8) adjusted for age, WHO PS, pre-ADT PSA, Gleason score, T-stage, N stage (N0, N1), metastatic volume if M1 (CHAARTED definition, high [M1HV] or low [M1LV]).

Likelihood ratio tests were used to test the hypotheses that Doce effect was larger in DS high vs lower. Primary endpoint was OS.

Updated OS (Feb 2024) included record linkage to national datasets. Hazard ratios (HR) provided with 95% confidence intervals.

Results

• 895 pts (539 M1, 356 M0, 639 [71%] reported to have died) were included and representative of the full trial cohort (N = 2369).
• DS were significantly lower in M0N0 (adjusted p<0.001) but showed the same distribution across M0N1, M1LV, M1HV.
• DS were prognostic: each 0.1 increment increased the hazards of death by 11% (HR = 1.11 [1.06-1.16], p<0.001) for M1, 9% (HR = 1.10 [1.02-1.18], p = 0.012) for M0.
• DS predicted Doce efficacy in M1: high DS, HR = 0.64 [0.48-0.86]; lower DS, HR = 0.96 [0.71-1.30].
• This interaction effect was statistically significant (p = 0.039). The effect was consistent in M1LV (high DS, HR = 0.53 [0.32-0.88]; lower DS, HR = 0.78 [0.47-1.30]) and M1HV (high DS, HR = 0.72 [0.49-1.07]; lower DS, HR = 1.16 [0.77-1.74]).
• In M0 there was no evidence of an interaction effect (p=0.302; high DS, HR = 0.75 [0.44-1.28]; lower DS, HR = 1.04 [0.68-1.59]).

Conclusions

High DS identifies synchronous M1 PC pts who benefit from Doce. DS is the 1st molecular classifier independent of metastatic volume to show a statistically significant interaction with Doce in directly randomised M1 PC pts.

Reference

Annals of Oncology (2024) 35 (suppl_2): S962-S1003. 10.1016/annonc/annonc1607

Alliance A031501: AMBASSADOR Study of Adjuvant Pembrolizumab (Pembro) in Muscle-invasive Urothelial Carcinoma (MIUC) vs Observation (Obs): Extended Follow-up Disease-free Survival (DFS) Results and Metastatic (met) Disease Recurrence Distribution

Background

The AMBASSADOR study (NCT03244384) demonstrated a significant improvement in DFS for adjuvant Pembro vs Obs in patients (pts) with high-risk MIUC after radical surgery.

Aim:

This study report extended DFS (19 additional median (m) months (mo)) follow-up data, sites of met recurrence, and lymph node (LN) status outcomes.

Methods

This is an open label, randomized, phase 3 trial that enrolled pts with MIUC of the bladder, upper tract (UT), or urethra. Pts were randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or Obs.

The dual primary endpoints were DFS and OS. Final OS analysis requires additional events.

Results

• 702 pts were randomized. mDFS follow-up was 41.3 mo. DFS benefit was seen in most subgroups analyzed including pathologic stage, +margins, NAC (yes/no), PD-L1 status (+/-), age, and ECOG PS.
• DFS benefit for UT ureter tumors was observed but not for renal pelvis tumors. DFS benefit with Pembro was seen in all pts with N0 and N+ stage and UT tumors with N+ stage.
• Common sites of met included LN, pelvic mass, lung, bone, liver (Table, *non-mutually exclusive; NE-Not Estimable).

	Pembro mDFS (95% CI), mo	N events/ N total	Obs mDFS (95% CI), mo	N events/ N total	HR (95% CI)
All pts	29.6 (21.8-41.9)	182/354	14.5 (11-20.2)	194/348	.72 (.59-.89)
UT Ureter	54.0 (43.8-NE)	10/28	17.7 (8.2-NE)	16/33	.58 (.26-1.32)
UT Renal Pelvis	26.6 (9.7-NE)	26/53	60.5 (60.5-NE)	11/40	1.99 (.98-4.02)
LN Status
All pts
N0	NE (NE-NE)	39/132	35.2 (18.1-NE)	67/148	.52 (.35-.77)
N+	14.5 (11.3-20)	121/186	8.8 (6.9-11.8)	119/174	.75 (.59-. 97)
UT pts
N0	NE (26.6-NE)	6/22	60.5 (30.2-NE)	13/36	.7 (.27-1.85)
N+	54.0 (8.2-NE)	12/27	17.7 (12.1-NE)	7/14	.95 (0.37-2.41)
DFS eventsMet Site %		N=147		N=165
Chest LN		17		8.5
Abdominal LN		23.1		32.7
Pelvic LN		21.8		24.2
Pelvic Mass		11.6		15.2
Lung		10.9		13.9
Bone		19.7		18.8
Liver		10.2		14.5

 

Conclusions

With extended DFS follow-up, Pembro continues to show DFS benefit vs Obs. All pts, including UT pts (trend) had DFS benefit with Pembro regardless of LN status (N0 or N+). Met recurrences were more common in pts on Obs vs Pembro and the sites of distribution were similar.

Reference

Annals of Oncology (2024) 35 (suppl_2): S1135-S1169. 10.1016/annonc/annonc1616

Tivozanib–nivolumab vs Tivozanib Monotherapy in Patients with Renal Cell Carcinoma (RCC) following 1 or 2 Prior Therapies Including an Immune Checkpoint Inhibitor (ICI): Results of the Phase III TiNivo-2 Study.

Background

The selective VEGFR TKI tivozanib has demonstrated single agent activity following VEGFR TKI and ICI, and in combination with ICI.

Aim

TiNivo-2 was designed to test the combination of the PD-1 inhibitor nivolumab and tivozanib vs tivozanib monotherapy following tumor progression on prior ICI-based therapy.

Methods

TiNivo-2 enrolled pts with advanced clear-cell RCC who had 1–2 prior lines of therapy, including an ICI. Pts were randomized to receive tivozanib (0.89 mg) plus nivolumab or tivozanib alone (1.34 mg).

The primary endpoint was PFS by independent radiology review (IRR); the key secondary endpoint was OS, other secondary endpoints included investigator-assessed PFS, ORR, DoR, and safety/tolerability.

A sample size of 343 pts with 220 events provided ≥80% power to detect a 50% improvement in PFS, 12 m vs 8 m, assessed by IRR.

Results

• 343 pts were randomized to tivozanib–nivolumab (n=171) or tivozanib (n=172). Baseline characteristics were well balanced.
• With a median IRR-assessed PFS of 5.7 m for tivozanib–nivolumab and 7.4 m for tivozanib (HR 1.10 [95% CI 0.82. 1.43]), the study did not meet its primary endpoint.
• Among those with ICI as immediate prior therapy (n=244), mPFS was 7.4 m (95% CI, 5·55-9·56) with tivozanib–nivolumab and 9.2 m (95% CI, 7·43-9·99) with tivozanib.
• Data for subgroups and OS and ORR are in the table. 205 (60%) pts experienced a grade 3 or higher AE, the most common was hypertension (22% both arms; others

Conclusions

ICI combination rechallenge did not improve clinical outcomes, suggesting the avoidance of sequential ICI in advanced RCC outside of clinical trials. These results support tivozanib monotherapy at 1.34 mg daily as 2nd-line therapy for pts following progression on previous ICI combination therapy.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Final Analysis of the Phase III LITESPARK-005 Study of Belzutifan versus Everolimus in Participants (pts) with Previously Treated Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

Background

Belzutifan significantly improved progression-free survival (PFS) and objective response rate (ORR) vs everolimus in pts with advanced ccRCC after immune checkpoint and antiangiogenic agents in LITESPARK-005 (NCT04195750).

Aim

This study reports final analysis of the phase III LITESPARK-005 study of belzutifan versus everolimus in pts with previously treated advanced ccRCC.

Methods

• Eligible pts were adults with advanced ccRCC and 1–3 prior systemic regimens including ≥1 PD-(L)1 inhibitor and ≥1 VEGFR-TKI. Pts were randomized 1:1 to belzutifan 120 mg or everolimus 10 mg QD until progression or unacceptable AEs.
• PFS per RECIST 1.1 by central review and overall survival (OS) were the dual primary endpoints. ORR per RECIST 1.1 by central review was a key secondary endpoint.
• Duration of response (DOR) and safety were secondary endpoints.
• No formal statistical testing was performed at final analysis (FA) for PFS and ORR as these endpoints were positive at first interim analysis.

Results

• 746 pts were allocated to belzutifan (n=374) or everolimus (n=372). At FA (data cutoff: April 15, 2024), median follow-up was 35.8 mo (range 26.9–49.2); 14.5% of pts had ongoing treatment with belzutifan vs 1.4% with everolimus.
• PFS benefit was maintained with belzutifan vs everolimus (median 5.6 mo vs 5.6 mo; HR 0.75; 95% CI 0.63–0.88); estimated PFS rate at 12 mo (33.7% vs 17.6%) and at 24 mo (17.5% vs 4.1%) favored belzutifan.
• Median OS was 21.4 mo with belzutifan vs 18.2 mo with everolimus (HR 0.92; 95% CI 0.77–1.10; P=0.18).
• Estimated OS rate was 67.9% vs 65.8% at 12 mo and 45.2% vs 41.2% at 24 mo. ORR was consistent with prior reports (22.7% vs 3.5%).
• Median (range) DOR was 19.3 mo (1.9+–40.1+) vs 13.7 mo (3.8–29.5+). Fewer pts discontinued belzutifan (6.2%) vs everolimus (15.3%) due to an any-cause AE.
• Median duration of therapy was longer with belzutifan (7.6 mo vs 3.9 mo). Rate of grade ≥3 TRAEs (39.5% vs 40.0%) was similar between arms.

Conclusions

Belzutifan continued to show PFS and ORR benefits vs everolimus, although significant improvement in OS was not observed. With >2 yrs minimum follow-up, the safety profile of belzutifan was consistent with prior reports. Final analysis results of LITESPARK-005 support belzutifan as a treatment option in advanced ccRCC after PD-(L)1 inhibitor and VEGFR-TKI therapy.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Enzalutamide (enza) with or without Leuprolide in Patients (pts) with High-risk Biochemically Recurrent (hrBCR) Prostate Cancer (PC): EMBARK Post Hoc Analysis by Age

Background

Pts diagnosed with PC aged >70 years (y) are at greater risk of PC-related death vs pts diagnosed aged ≤70 y. In EMBARK, enza ± leuprolide significantly prolonged metastasis-free survival (MFS) by blinded independent central review vs leuprolide alone in pts with PC and hrBCR.

Aim

Here, this study present a post hoc analysis of outcomes by age.

Methods

EMBARK, a phase 3 trial (NCT02319837), included pts after local therapy with hrBCR: prostate-specific antigen (PSA) doubling time ≤9 months and PSA ≥2 ng/mL above nadir post radiotherapy (RT) or ≥1 ng/mL after radical prostatectomy (RP) ± postoperative RT. Pts were randomised (1:1:1) to enza + leuprolide (combo), leuprolide alone, or enza monotherapy (mono).

A post hoc analysis of MFS and safety by median age in EMBARK was conducted (<70 vs ≥70 y).

Results

• In total, 543 pts (50.8%) were aged

Conclusions

In this post hoc analysis from EMBARK, similar treatment benefits for enza combo and mono vs leuprolide alone were seen in pts with hrBCR aged <70 and ≥70 y. Tx-related serious AEs were more common in older pts, but were low regardless of age.

Reference

Annals of Oncology (2024) 35 (suppl_2): S962-S1003. 10.1016/annonc/annonc1607

 

Open-label, Multicentre Randomised Trial of Radium223-Docetaxel versus Docetaxel-Radium223 Sequence in Metastatic Castration Resistant Prostate Cancer (mCRPC) with Prospective Biomarker Evaluation (RAPSON Study)

 

Background

Defining the most effective treatment sequence between α emitter Radium223 and docetaxel is pivotal for optimizing bone-dominant mCRPC outcomes.

Aim

This study evaluates Radium223-docetaxel versus docetaxel-Radium223 sequence in metastatic castration resistant prostate cancer (mCRPC) with prospective biomarker.

Methods

RAPSON is a prospective, multicentre, randomized phase 2 trial in 70 patients (pts) with symptomatic bone-dominant mCRPC who progressed after androgen deprivation therapy ± abiraterone or enzalutamide. Pts were initially randomized 1:1 to receive Radium223 or docetaxel as first treatment followed by docetaxel or Radium223, respectively, at progression. The primary endpoint was the impact of sequential therapy on the percentage of pts with symptomatic bone-dominant mCRPC experiencing changes in health-related quality of life (QoL) measured with the Functional Assessment of Cancer Therapy Prostate (FACT-P) questionnaire from baseline to week 12. The upper limit of the minimally important difference (MID) range was used to evaluate these changes. Pts experiencing a QoL increase ≥MID of FACT-P questionnaire were considered responders, whereas pts experiencing a decrease in QoL score ≥MID were considered no responders.

Results

At median follow-up of 13 months (range 4-45), a preliminary responder analysis at week 12 showed 33% vs 50% of pts experiencing a worsening of FACT-P questionnaire score (22% vs 50% in the physical well-being subscale) in Radium223 vs docetaxel arm, respectively. The mean change in FACT-P total scores from baseline to week 12 was 4 [Standard Deviation (SD) 16.84 for Radium223 and 7.87 (SD 14.08) for docetaxel, with a difference between groups of 3.87 (95% CI -9.14 to 16.89). Radium223 -> docetaxel resulted in an improvement of QoL compared to docetaxel -> Radium223, also in terms of better tolerability (2 vs 7 discontinuations, and 1 vs 9 dose reductions related to Radium223 vs docetaxel, respectively). Efficacy results reported no difference in PFS and OS between Radium223 and docetaxel evaluated only for step 1 as only 14 pts completed step 2 so far.

Conclusions

RAPSON trial provided evidence to support the use of Radium223 prior to chemotherapy in bone-dominant symptomatic mCRPC with a clinical benefit in terms of better QoL and tolerability.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Cabozantinib (C) Plus Atezolizumab (A) versus 2nd Novel Hormonal Therapy (NHT) in Patients (Pts) with Metastatic Castration-resistant Prostate Cancer (mCRPC): Final Overall Survival (OS) Results of the Phase III, Randomized, CONTACT-02 Study

Background

Pts with mCRPC whose disease progressed on NHT have a poor prognosis and limited treatments. C+A significantly prolonged progression-free survival (PFS) vs NHT in CONTACT-02 (HR 0.65; 95% CI 0.50, 0.84; P=0.0007), meeting 1 of the study’s 2 primary endpoints.

Aim

This study aims to present the final analysis of the 2nd primary endpoint, OS.

Methods

Pts with mCRPC whose disease progressed on one prior NHT and who had measurable extrapelvic nodal or visceral disease were randomized 1:1 to C+A or NHT (abiraterone + prednisone or enzalutamide).

Dual primary endpoints were BIRC-assessed PFS (first 400 pts; PFS ITT) and OS (all randomized pts; ITT).

Results

• At the data cutoff (median follow-up 24.0 mo), 575 pts were randomized to C+A (n=289) or NHT (n=286).
• Baseline characteristics were balanced between treatment arms: 79%/76% had bone metastasis (BM), 23%/23% had liver metastases (LM), and 22%/22% had received prior docetaxel.
• Follow-on systemic therapy was received in 49% and 56% (36% and 49% received a post-study taxane).
• Efficacy data are shown, below.
• Treatment-related grade 3-4 AEs occurred in 40% of the C+A study arm and in 8% of the NHT arm.
• There were no grade 5 treatment-related AEs. TEAEs led to discontinuation of all treatment components in 17% (C+A) and 15% (NHT). 

	ITTN=575	BM n=446	LM n=132	Prior Docetaxel n=126
OS HR (ITT)	0.89 (0.72, 1.10) P=0.296	0.79 (0.63, 1.00) P=0.046	0.68 (0.47, 1.00) P=0.051	0.71 (0.46, 1.09) P=0.117
Median OS (C+A); mo	14.78 (13.37, 16.66)	13.80 (11.93, 16.33)	12.19 (8.80, 13.80)	13.37 (9.89, 20.93)
Median OS (NHT); mo	14.98 (13.01, 18.50)	11.56 (10.45, 14.06)	7.06 (5.32, 10.38)	11.53 (9.07, 17.02)
PFS ITT	n=400	n=317	n=99	n=89
PFS HR	0.65 (0.50, 0.84) P

 

Conclusions

CONTACT-02 was a positive study meeting one of the dual primary endpoints of PFS; the combination of cabozantinib and atezolizumab was superior to NHT (HR 0.65). Final OS, the 2nd dual primary endpoint, favored C + A (HR 0.89), but did not achieve statistical significance. A survival advantage was seen in some subgroups (e.g. liver metastasis, bone metastasis) The tolerability profile of C+A was similar to other approved TKI/ICI combinations in pts with advanced cancers.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Alliance A031501: AMBASSADOR Study of Adjuvant Pembrolizumab (Pembro) in Muscle-invasive Urothelial Carcinoma (MIUC) vs Observation (Obs): Extended Follow-up Disease-free Survival (DFS) Results and Metastatic (met) Disease Recurrence Distribution

Background

The AMBASSADOR study (NCT03244384) demonstrated a significant improvement in DFS for adjuvant Pembro vs Obs in patients (pts) with high-risk MIUC after radical surgery.

Aim

The aim of the study is to report extended DFS (19 additional median (m) months (mo)) follow-up data, sites of met recurrence, and lymph node (LN) status outcomes.

Methods

This is an open label, randomized, phase 3 trial that enrolled pts with MIUC of the bladder, upper tract (UT), or urethra.

Pts were randomized 1:1 to receive Pembro 200 mg every 3 weeks for 1 year or Obs. The dual primary endpoints were DFS and OS.

Final OS analysis requires additional events.

Results

• 702 pts were randomized. mDFS follow-up was 41.3 mo.
• DFS benefit was seen in most subgroups analyzed including pathologic stage, +margins, NAC (yes/no), PD-L1 status (+/-), age, and ECOG PS.
• DFS benefit for UT ureter tumors was observed but not for renal pelvis tumors. DFS benefit with Pembro was seen in all pts with N0 and N+ stage and UT tumors with N+ stage.
• Common sites of met included LN, pelvic mass, lung, bone, liver (Table, *non-mutually exclusive; NE-Not Estimable).

	Pembro mDFS (95% CI), mo	N events/ N total	Obs mDFS (95% CI), mo	N events/ N total	HR (95% CI)
All pts	29.6 (21.8-41.9)	182/354	14.5 (11-20.2)	194/348	.72 (.59-.89)
UT Ureter	54.0 (43.8-NE)	10/28	17.7 (8.2-NE)	16/33	.58 (.26-1.32)
UT Renal Pelvis	26.6 (9.7-NE)	26/53	60.5 (60.5-NE)	11/40	1.99 (.98-4.02)
LN Status
All pts
N0	NE (NE-NE)	39/132	35.2 (18.1-NE)	67/148	.52 (.35-.77)
N+	14.5 (11.3-20)	121/186	8.8 (6.9-11.8)	119/174	.75 (.59-. 97)
UT pts
N0	NE (26.6-NE)	6/22	60.5 (30.2-NE)	13/36	.7 (.27-1.85)
N+	54.0 (8.2-NE)	12/27	17.7 (12.1-NE)	7/14	.95 (0.37-2.41)
DFS eventsMet Site %		N=147		N=165
Chest LN		17		8.5
Abdominal LN		23.1		32.7
Pelvic LN		21.8		24.2
Pelvic Mass		11.6		15.2
Lung		10.9		13.9
Bone		19.7		18.8
Liver		10.2		14.5

 

Conclusions

With extended DFS follow-up, Pembro continues to show DFS benefit vs Obs. All pts, including UT pts (trend) had DFS benefit with Pembro regardless of LN status (N0 or N+). Met recurrences were more common in pts on Obs vs Pembro and the sites of distribution were similar.

Reference

Annals of Oncology (2024) 35 (suppl_2): S1135-S1169. 10.1016/annonc/annonc1616

A Randomized Multicenter Open Label Phase III Trial Comparing Enzalutamide vs a Combination of Radium-223 (Ra223) and Enzalutamide in Asymptomatic or Mildly Symptomatic Patients with Bone Metastatic Castration-resistant Prostate Cancer (mCRPC): First Results of EORTC-GUCG 1333/PEACE-3

Background

PEACE-3, an EORTC/CTI/CUOG/LACOG/UNICANCER cooperative study, investigates whether the combination of Enzalutamide and Ra223 (ENZ-RAD) improves cancer progression over Enzalutamide alone (ENZ) in patients with mCRPC.

Aim

This study aims to compare enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone mCRPC

Methods

Men with mCRPC and bone metastases were randomized 1:1 to ENZ or ENZ-RAD. As of 03/2018, co-administration of zoledronic acid or denosumab was obligatory.

The primary endpoint was radiological progression-free survival (rPFS).

Secondary endpoints include overall survival (OS), time to subsequent systemic anti-neoplastic therapy, time to pain progression, and time to first symptomatic skeletal event.

Results

• From 11/2015 to 03/2023, 446 men were enrolled.
• The median age was 70 years (IQR: 65-76).
• The median follow-up duration was 42.2 months (mo); 87.9 % of patients in the ENZ-RAD arm who started Ra223 completed the scheduled 6 cycles.
• The hazard ratio (HR) for rPFS was 0.69 (95% CI 0.54-0.87; p=0.0009), with a median rPFS of 16.4 (95%CI 13.8-19.2) mo in the ENZ arm and 19.4 (95%CI 17.1-25.3) mo in the ENZ-RAD arm.
• The HR for OS was 0.69 (95% CI 0.52-0.90; p=0.0031), with median OS in the preplanned interim analysis, performed at 80% of events, of 35.0 (95%CI 28.8-38.9) mo in the ENZ arm and 42.3 (95%CI 36.8-49.1) mo in the ENZ-RAD arm.
• The study will proceed to final OS analysis because of non-proportionality. Treatment-emergent adverse events (TEAE) ≥ grade 1 were reported in 96.4% and 100%, ≥ grade 3 in 55.8% and 65.6% of the patients in ENZ and ENZ-RAD, respectively.
• Most frequent grade ≥ 3 TEAE in the ENZ-RAD arm were hypertension (34%), fatigue (6%), anemia (5%), and neutropenia (5%).
• No TEAE ≥ grade 3 was increased by more than 5% in the ENZ-RAD arm vs the ENZ arm.

Conclusions

PEACE-3 demonstrates that adding 6 cycles of Ra223 to enzalutamide as first-line therapy for mCRPC significantly improves rPFS. An interim analysis shows a statistically significant OS benefit favoring the ENZ-RAD combination, and a final OS analysis will be performed for further confirmation of this result.

Reference

Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623