ERLEADA – TITAN Study

Overview¹

TITAN (NCT02489318) was a phase 3, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of ERLEADA compared with placebo in patients with mCSPC

N=1052

An overview of the TITAN study design and results is available in video format: LINK.

Key Eligibility Criteria¹

mCSPC
Metastatic disease documented by ≥1 lesion on bone scan
With or without visceral or lymph node metastasis
ECOG PS 0 or 1

Prior therapy limitations:

^aMaximum 6 cycles, no evidence of progression during treatment or before randomization

Study Design^1,2

^aAll patients received ADT via a GnRH analog or surgical castration.
^bBased on results from this first planned interim analysis, the IDMC recommended unblinding to allow crossover of patients (without progression) receiving placebo to receive apalutamide.

Efficacy Results^1,3

The dual primary endpoints for the primary and final analyses are described below.

Endpoints	ERLEADA (n=525)	Placebo (n=527)
Primary Analysis
Median rPFS, months	NE	22.1
HR (95% CI); P-value	0.48 (0.39-0.60); <0.001
Median OS, months	NE	NE
HR (95% CI); P-value	0.67 (0.51-0.89); 0.005
Final Analysis^a
Median OS, months	NR	52.2
HR (95% CI); P-value	0.65 (0.53-0.79); <0.0001

^aThe final analysis provided mature OS results without formal statistical inference.

Safety Results^3,4

All-grade TEAEs reported during the final analysis are described below.

AEs, n (%)	ERLEADA (n=524)	Placebo (n=527)
≥1 TEAE^a	510 (97.3)	510 (96.8)
Serious TEAE^a	153 (29.2)	115 (21.8)
Leading to treatment discontinuation	62 (11.8)	30 (5.7)
Leading to death	20 (3.8)	17 (3.2)
Treatment-related TEAEs (≥5% of patients)
≥1 treatment-related TEAE	319 (60.9)	221 (41.9)
Rash	92 (17.6)	12 (2.3)
Pruritus	43 (8.2)	13 (2.5)
Fatigue	71 (13.5)	46 (8.7)
Hot flush	67 (12.8)	52 (9.9)
Hypertension	28 (5.3)	21 (4.0)

^aGrade 5 events were excluded.

Additional Analyses^5-33

Additional analyses evaluated efficacy, safety, and HRQoL in patients based on age, disease volume, number of metastases, timing of metastasis presentation, D0 or D1 at diagnosis, prior docetaxel treatment, exposure, PSA kinetics and relationship to rPFS, OS and HRQoL, high- and low-risk mCSPC, PFS2 by first subsequent therapy (specifically hormonal vs taxane therapy) after discontinuing study treatment, and use with or without concomitant OACs.
Additional analyses evaluating molecular signatures, subtypes, and androgen receptor activity and aberrations with long term outcomes have been reported.
Patient subgroup analyses were conducted in Latin American, Japanese, and East Asian patients.

Note: ADT, androgen deprivation therapy; AE, adverse event; CI, confidence interval; D0, progression to mCSPC after localized disease; D1, de novo mCSPC; ECOG PS, Eastern Cooperative Oncology Group Performance Status; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; IDMC, independent data-monitoring committee; mCSPC, metastatic castration-sensitive prostate cancer; NE, not estimable; NR, not reached; OAC, oral anticoagulant; OS, overall survival; PFS2, second progression-free survival; PO, orally; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival; TEAE, treatment-emergent adverse event.

TITAN (NCT02489318) was a phase 3, randomized, double-blind, placebo-controlled, multicenter study conducted at 260 sites in 23 countries within North America, Central America, South America, Europe, and Asia-Pacific that evaluated the efficacy and safety of ERLEADA plus ADT compared with placebo plus ADT in patients with mCSPC (N=1052).^1-3,34
All patients were required to have a documented diagnosis of adenocarcinoma of the prostate, distant metastatic disease (≥1 lesion on bone scan, with or without visceral or lymph node involvement), and castration-sensitive disease (ie, patients who are not receiving ADT at the time of progression).¹

^aPatients who had received a GnRH agonist ≤28 days before randomization were required to take a first-generation antiandrogen for ≥14 days before randomization, and the antiandrogen must have been discontinued before randomization. Patients were assessed for eligibility (≤6 weeks before randomization) and efficacy (during treatment cycles 3 and 5 and every fourth cycle thereafter) per modified RECIST version 1.1 using CT or MRI of the chest, abdomen, and pelvis and per PCWG2 criteria via bone scan.
^bMaximum 6 cycles, no evidence of progression during treatment or before randomization.
^cSuch as radiation therapy and prostatectomy.
^dAll patients received ADT via a GnRH analog or surgical castration.
^eIn the final analysis, OS results did not include formal statistical inference and the updated analyses presented for secondary endpoints were based on the final data cutoff and performed without formal statistical retesting. The final formal statistical testing for all secondary endpoints was performed at the time of the first interim analysis.

Dual Primary Endpoints¹

rPFS^a
OS

Secondary Endpoints^1,34

Time to initiation of cytotoxic chemotherapy
Time to pain progression, assessed by BPI-SF item 3 (worst pain)
Time to skeletal-related event^b
Time to chronic opioid use

Exploratory Endpoints^1,28,36

Time to PSA progression^c
PFS2^d
Time to symptomatic local progression
PROs, assessed by the FACT-P questionnaire, EuroQoL EQ-5D-5L questionnaire, BFI, and BPI-SF

Ad Hoc Endpoint⁴

Time to castration resistance^e

Secondary Objective¹

A prespecified analysis of treatment outcomes for patients with low- or high-volume^f mCSPC was evaluated.

^aDefined as time from randomization to first imaging-based documentation of disease progression (progression of soft tissue lesions measured by CT or MRI or new bone lesions on bone scan) or death, whichever occurred first.
^bDefined as time from randomization to first observation of a skeletal-related event (symptomatic pathologic fracture, spinalcord compression, radiation to bone, or surgery to bone).
^cDefined as time from randomization to PSA progression per PCWG2 criteria.
^dDefined as time from randomization to first occurrence of investigator-assessed disease progression (PSA progression, progression on imaging, or clinical progression) while the patient was receiving first subsequent treatment for prostate cancer or death from any cause, whichever occurred first.
^eDefined as time from randomization to radiographic disease progression, PSA progression per PCWG2, or symptomatic skeletal event, whichever occurred first.
^fLow-volume mCSPC was defined as the presence of bone lesions not meeting the high-volume disease definition, and high-volume mCSPC was defined as visceral metastases and ≥1 bone lesion or ≥4 bone lesions with ≥1 outside the axial skeleton.

Patient demographic and disease characteristics were well balanced between the 2 groups, and there were no substantial differences.¹
Most patients were found to have metastatic disease at initial prostate cancer diagnosis (ERLEADA group, 78.3%; placebo group, 83.7%), and 62.7% of patients met the criteria for high-volume mCSPC compared with 37.3% with low-volume mCSPC.¹
Over 70% of patients in both groups described having no pain (score 0) or mild pain (score 1-3) at baseline based on mean BPI-SF pain score results; the median baseline FACT-P total score was 113 for both groups (scores range from 0 to 156; higher scores indicate more favorable HRQoL).^1,32

Select Baseline Patient and Disease Characteristics^1,34

	ERLEADA Group (n=525)	Placebo Group (n=527)
Median age, years (range)	69 (45-94)	68 (43-90)
Race, n (%)
White	354 (67.4)	365 (69.3)
Asian	119 (22.7)	110 (20.9)
Black or African American	10 (1.9)	9 (1.7)
American Indian or Alaska Native	6 (1.1)	13 (2.5)
Not reported	11 (2.1)	8 (1.5)
Other	24 (4.6)	22 (4.2)
Multiple	1 (0.2)	0
ECOG PS score, n (%)
0	328 (62.5)	348 (66.0)
1	197 (37.5)	178 (33.8)
2	0	1 (0.2)
Median time from initial diagnosis to randomization, months (range)	4.1 (0.5-222.9)	4.0 (0.7-341.4)

After unblinding of the study, 208 (39.5%) patients in the placebo group without disease progression received therapy with ERLEADA plus ADT (crossover group).³

At the clinical cutoff date, 66.2% and 46.1% of patients in the ERLEADA and placebo groups remained on treatment, respectively.¹
At the final analysis for rPFS (following 365 events), treatment with ERLEADA significantly improved rPFS with a 52% risk reduction in radiographic progression or death (median rPFS was NE in the ERLEADA group and 22.1 months in the placebo group; HR, 0.48; 95% CI, 0.39-0.60; P<0.001).¹
- The percentage of patients with rPFS at 24 months was 68.2% and 47.5% in the ERLEADA and placebo groups, respectively.
- The treatment effect of ERLEADA on rPFS was consistently favorable across prespecified subgroups, including prior docetaxel use and disease volume (high volume: HR, 0.53; 95% CI, 0.41-0.67; low volume: HR, 0.36; 95% CI, 0.22-0.57).
At the first interim analysis for OS (following 200 deaths), treatment with ERLEADA significantly improved OS with a 33% risk reduction in death (median OS was NE in either group; HR, 0.67; 95% CI, 0.51-0.89; P=0.005).¹
- The OS percentage at 24 months was 82.4% and 73.5% in the ERLEADA and placebo groups, respectively.
- The treatment effect on OS consistently favored ERLEADA over placebo across prespecified subgroups, with no difference based on disease volume (high volume: HR, 0.68; 95% CI, 0.50-0.92; low volume: HR, 0.67; 95% CI, 0.34-1.32).
Time to cytotoxic chemotherapy was significantly longer in the ERLEADA group compared with the placebo group (HR, 0.39; 95% CI, 0.27-0.56; P<0.001).¹
Based on preplanned hierarchical testing sequence, formal significance testing was not performed for the other secondary endpoints because there was no significant difference between the groups for time to pain progression (P=0.12).¹

The final analysis for OS was performed after 405 deaths (170 patients in the ERLEADA group and 235 patients in the placebo group) and a median follow-up of 44.0 months.¹
An improvement in median OS was observed: NR in the ERLEADA group vs 52.2 months in the placebo group (HR, 0.65; 95% CI, 0.53-0.79; P<0.0001), with a 35% risk reduction in death. OS results did not include formal statistical inference, and the updated analyses presented for secondary endpoints were based on the final data cutoff and performed without formal statistical retesting. The final formal statistical testing for all secondary endpoints was performed at the time of the first interim analysis.³
- Based on a prespecified sensitivity analysis for OS that accounted for ~40% crossover from the placebo group to the ERLEADA group using the IPCW log-rank test, there was a 48% risk reduction in death after adjusting for crossover (median, NR vs 39.8 months in the ERLEADA group vs placebo group; HR, 0.52; 95% CI, 0.42-0.64; P<0.0001).
- The treatment effect of ERLEADA on OS was favorable across certain prespecified subgroups, including patients with high- and low-volume mCSPC (HR, 0.70; 95% CI, 0.56-0.88 and HR, 0.52; 95% CI, 0.35-0.79, respectively) and high-risk patients (HR, 0.57; 95% CI, 0.45-0.73). The interaction effect between treatment and the subgroup with bone metastases only at baseline was statistically significant for OS (P=0.0108).
At treatment discontinuation, 247 (47.0%) patients in the ERLEADA group and 345 (65.5%) patients in the placebo group were alive, of whom 36.0% (n=89) and 50.1% (n=173) received first life-prolonging subsequent therapy, respectively.³
- Of 138 patients in the ERLEADA group and 261 patients in the placebo group who were alive and discontinued because of progressive disease, 54.3% and 57.9%, respectively, received first life-prolonging subsequent therapy, most commonly docetaxel and abiraterone acetate plus prednisone.
- Among 109 patients in the ERLEADA group and 84 patients in the placebo group who were alive and discontinued for other reasons, 12.8% and 26.2%, respectively, also received first life-prolonging subsequent therapy.
- Overall, of 527 patients in the placebo group, 173 (32.8%) received first life-prolonging subsequent therapy. Together with 208 (39.5%) patients in the placebo group who crossed over to receive ERLEADA, 381 (72.3%) patients in the placebo group received active life-prolonging subsequent treatment after study treatment discontinuation.
Median total FACT-P scores indicated HRQoL remained stable in the ERLEADA group, with no substantial differences between treatment groups. Specific HRQoL domains, measured by FACT-P subscales, were also maintained in the ERLEADA group.^3,4
There were no significant differences between treatment groups in median TTD in any FACT-P or BPI scores.³⁷

The safety population included all patients who received ≥1 dose of study drug; 1 patient in the ERLEADA group discontinued the study prior to receiving a dose.¹
Treatment discontinuation due to progressive disease was reported in 99 (18.9%) vs 227 (43.1%) patients in the ERLEADA vs placebo group.¹
Ischemic heart disease was reported in 4.4% vs 1.5% of patients in the ERLEADA vs placebo group; 2 patient deaths due to ischemic events were reported in each group.¹
AEs associated with death in 10 patients in the ERLEADA group included acute kidney injury (n=2), acute MI, MI, cardiogenic shock, sudden cardiac death, cardio-respiratory arrest, respiratory failure, cerebrovascular accident, and large intestinal ulcer perforation (all n=1).³⁴
AEs associated with death in 16 patients in the placebo group included sudden death (n=2), respiratory failure (n=2), acute MI, acute coronary syndrome, cardiac failure, intracranial hemorrhage, subdural hemorrhage, vascular rupture, pulmonary embolism, sepsis, urosepsis, hypothermia, suicide, and unspecified death (all n=1).³⁴

Summary of AEs^1,34

AE, n (%)	ERLEADA Group (n=524)		Placebo Group (n=527)
AE, n (%)	Any Grade	Grade 3-4	Any Grade	Grade 3-4
Any AE	507 (96.8)	221 (42.2)	509 (96.6)	215 (40.8)
Serious AE	104 (19.8)	-	107 (20.3)	-
AE leading to treatment discontinuation^a	42 (8.0)	-	28 (5.3)	-
AE leading to death	10 (1.9)	-	16 (3.0)	-
AEs reported in ≥10% of patients or grade ≥3 in ≥10 patients in either group^b
Hot flush	119 (22.7)	0	86 (16.3)	0
Fatigue	103 (19.7)	8 (1.5)	88 (16.7)	6 (1.1)
Hypertension	93 (17.7)	44 (8.4)	82 (15.6)	48 (9.1)
Back pain	91 (17.4)	12 (2.3)	102 (19.4)	14 (2.7)
Arthralgia	91 (17.4)	2 (0.4)	78 (14.8)	5 (0.9)
Pain in arm or leg	64 (12.2)	3 (0.6)	67 (12.7)	5 (0.9)
Pruritus	56 (10.7)	1 (0.2)	24 (4.6)	1 (0.2)
Weight increased	54 (10.3)	6 (1.1)	89 (16.9)	10 (1.9)
Anemia	48 (9.2)	9 (1.7)	71 (13.5)	17 (3.2)
Constipation	47 (9.0)	0	57 (10.8)	0
Asthenia	37 (7.1)	10 (1.9)	44 (8.3)	3 (0.6)
Bone pain	34 (6.5)	6 (1.1)	53 (10.1)	9 (1.7)
Rash (generalized)	34 (6.5)	14 (2.7)	5 (0.9)	2 (0.4)
Blood ALP increased	16 (3.1)	2 (0.4)	28 (5.3)	13 (2.5)
Urinary retention	13 (2.5)	4 (0.8)	19 (3.6)	10 (1.9)
^aRash was the most common AE leading to treatment discontinuation (2.3% vs 0.2%), dose reduction (5.3% vs 0.8%), and dose interruption (8.4% vs 0.9%) in the ERLEADA group vs the placebo group, respectively. ^bShown are AEs of any cause that occurred from the time of the first dose of the trial intervention through 30 days after the last dose. AEs were assessed monthly and graded according to NCI CTCAE, version 4.0.3. One patient who was assigned to the ERLEADA group withdrew consent before treatment.

In the ERLEADA vs placebo vs crossover group, safety results are as follows³:
- The median treatment duration was 39.3 vs 20.2 vs 15.4 months.
- Adjusting for the difference in duration of exposure, rates of TEAEs of interest per 100 patient-years were 40.0 vs 22.4 vs 41.9.
- Progressive disease was the most frequent reason for treatment discontinuation and was reported in 138 (26.3%) vs 245 (76.8%) vs 16 (7.7%) patients.
- Total patient-years of exposure was 1358.9 vs 793.3 vs 243.6.
There were no treatment-related deaths.³

Summary of AEs^3,4

AE,^a n (%)	ERLEADA Group (n=524)		Placebo Group (n=527)		Crossover Group (n=208)
AE,^a n (%)	All Grades	Grade ≥3	All Grades	Grade ≥3	All Grades	Grade ≥3
≥1 TEAE,^b	510 (97.3)	259 (49.4)	510 (96.8)	220 (41.7)	174 (83.7)	57 (27.4)
Any serious TEAE,^b	153 (29.2)	-	115 (21.8)	-	29 (13.9)	-
Any TEAE leading to treatment discontinuation	62 (11.8)	-	30 (5.7)	-	16 (7.7)	-
TEAE leading to death	20 (3.8)	-	17 (3.2)	-	7 (3.4)	-
Any COVID-19 AE	0	-	0	-	3 (1.4)^c	-
Most frequent TEAEs (occurring in ≥10% of patients)
Back pain	108 (20.6)	-	111 (21.1)	-	11 (5.3)	-
Arthralgia	103 (19.7)	-	82 (15.6)	-	15 (7.2)	-
Pain in extremity	70 (13.4)	-	67 (12.7)	-	8 (3.8)	-
Fatigue	107 (20.4)	-	89 (16.9)	-	15 (7.2)	-
Bone pain	39 (7.4)	-	54 (10.2)	-	2 (1.0)	-
Rash	106 (20.2)	-	23 (4.4)	-	26 (12.5)	-
Pruritus	58 (11.1)	-	25 (4.7)	-	13 (6.3)	-
Constipation	59 (11.3)	-	58 (11.0)	-	6 (2.9)	-
Diarrhea	56 (10.7)	-	35 (6.6)	-	11 (5.3)	-
Hot flush	121 (23.1)	-	87 (16.5)	-	3 (1.4)	-
Hypertension	102 (19.5)	-	84 (15.9)	-	13 (6.3)	-
Weight increased	55 (10.5)	-	92 (17.5)	-	7 (3.4)	-
Anemia	69 (13.2)	-	72 (13.7)	-	13 (6.3)	-
^aShown are AEs of any cause, unless otherwise noted, that occurred from the time of the first dose of the trial intervention through 30 days after the last dose. For each category, patients with multiple events were counted only once. AEs were assessed monthly and graded according to NCI CTCAE, version 4.0.3. One patient who was assigned to the ERLEADA group withdrew consent before treatment. ^bExcludes grade 5 events. ^cThree patients in the crossover group reported COVID-19 TEAEs which resolved and did not lead to treatment discontinuation or death.

A post hoc analysis that evaluated depth of PSA reduction and long-term outcomes determined that 68% of patients achieved undetectable PSA levels (≤0.2 ng/mL) in the ERLEADA group compared with 32% in the placebo group and 90% and 73% of patients, respectively, had an overall ≥50% and ≥90% decline in PSA response in the ERLEADA group compared with 55% and 29% in the placebo group. Achievement of deep PSA decline (≥90% PSA decline or PSA ≤0.2 ng/mL) at 3 months of ERLEADA initiation was associated with improved OS (HR, 0.35; 95% CI, 0.25-0.48), rPFS (HR, 0.44; 95% CI, 0.30-0.65), time to PSA progression (HR, 0.31; 95% CI, 0.22-0.44), and time to castration resistance (HR, 0.38; 95% CI, 0.27-0.52); P≤0.0001 for all. Similar results were seen at 6 and 12 months of ERLEADA initiation.¹⁰

PSA Relationship to rPFS and OS

In another post hoc analysis that evaluated PSA kinetics (PSA50, PSA90, and PSA ≤0.2 ng/mL) and rPFS in the TITAN study, patients in the ERLEADA group achieved PSA50, PSA90, and PSA ≤0.2 ng/mL as early as 3 months after initiation of ERLEADA, with a median time to achieve a PSA50 response of 1 month. Patients in the ERLEADA group who achieved PSA50, PSA90, and PSA ≤0.2 ng/mL were at lower risk of radiographic progression compared with patients who did not achieve these responses (median rPFS for patients in the ERLEADA group with vs without PSA50, PSA90, and PSA ≤0.2 ng/mL: NR vs 18.3 months [HR, 0.27; 95% CI, 0.17-0.43], NR vs 28.7 months [HR, 0.46; 95% CI, 0.32-0.65], and NR vs 18.4 months [HR, 0.19; 95% CI, 0.14-0.27], respectively; all P<0.0001). At 6 months, the median rPFS was 18.3 months, 28.7 months, and NR for patients treated with ERLEADA who achieved a PSA response of <50%, 50% to <90%, and ≥90%, respectively.¹¹
In another post hoc analysis that evaluated the relationship between depth of PSA decline and OS reported that patients in the ERLEADA group who achieved PSA50, PSA90, and PSA ≤0.2 ng/mL achieved significant improvement in OS compared with those who did not achieve these responses (median OS for patients with vs without PSA50, PSA90, and PSA ≤0.2 ng/mL, respectively, in the ERLEADA group: NR vs 35.0 months [HR, 0.38; 95% CI, 0.25-0.59], NR vs 45.2 months [HR, 0.44; 95% CI, 0.32-0.60], and NR vs 30.0 months [HR, 0.17; 95% CI, 0.13-0.23]; all P<0.0001). Shorter time to undetectable PSA (≤0.2 ng/mL) correlated with longer OS time (rank correlation, -0.5; 95% CI, -0.6 to -0.4; P<0.05).¹²

PSA Relationship to HRQoL

In a post hoc analysis of the TITAN study, rapid and deep PSA decline (defined as a decline of ≥90% from baseline or to ≤0.2 ng/mL) correlated with HRQoL measures (ie, time to worsening in FACT-P total score, worsening in FACT-P physical wellbeing subscale score, BPI-SF worst pain intensity progression, or BFI worst fatigue intensity progression) at 3 and 6 months following treatment with ERLEADA added to ADT.²⁷

Effect of Ultra-Low PSA on Clinical Outcomes

In another analysis that evaluated the effect of ultra-low PSA (≤0.2 ng/mL) on clinical outcomes in patients with mCSPC in the TITAN study, the percentage of patients achieving ultra-low 1 (>0.02 to ≤0.2 ng/mL) and ultra-low 2 (≤0.02 ng/mL) PSA levels with ERLEADA vs placebo at any time was 19% and 49% vs 14% and 17%, respectively. OS and rPFS were significantly improved in patients with ultra-low 1 (OS: HR, 0.46; 95% CI, 0.31-0.67; P<0.0001; rPFS: HR, 0.54; 95% CI, 0.35-0.83; P=0.0047) and ultra-low 2 (OS: HR, 0.24; 95% CI, 0.13-0.43; P<0.0001; rPFS: HR, 0.28; 95% CI, 0.14-0.54; P=0.0002) PSA at the end of 3 months. Compared with patients with PSA >0.2 ng/mL, improved OS was seen in patients who achieved ultra-low 2 PSA in 3 months (HR, 0.12; 95% CI, 0.06-0.22; P<0.0001) or 3-6 months (HR, 0.14; 95% CI, 0.08-0.27; P<0.0001) vs in patients who achieved it after 6 months (HR, 0.25; 95% CI, 0.17-0.36; P<0.0001) or did not achieve it at all. The occurrence of TEAEs was similar between the ERLEADA and placebo groups among the PSA response subgroups (PSA >0.2 ng/mL, ultra-low 1, and ultra-low 2) at 3 months.³²

Early PSA Response

In an exploratory secondary analysis that evaluated whether early PSA response (defined as achieving a PSA level of ≤0.2 ng/mL by 6 months of randomization) was predictive of treatment efficacy, 61% of patients in the ERLEADA group and 24% of patients in the placebo group achieved an early PSA response. The ERLEADA group was associated with improved OS in 6-month PSA responders (HR, 0.66; 95% CI, 0.44-1.00) vs nonresponders (HR, 1.14; 95% CI, 0.89-1.46), with a differential treatment effect between groups stratified by early PSA response by 6 months (P=0.03); no significant difference was observed at 3 months (P=0.17). In the ERLEADA vs placebo group, 3-year confounder-adjusted OS was 84% (80%-88%) vs 74% (66%-82%) among 6-month PSA responders and 58% (52%-65%) vs 56% (51%-60%) among nonresponders.³³

A post hoc analysis evaluated the efficacy and safety outcomes for patients with baseline high- and low-risk mCSPC enrolled in the TITAN study.¹³
- High-risk mCSPC was defined as ≥2 of the following risk factors: Gleason score of ≥8, ≥3 bone lesions, and presence of measurable visceral metastasis.
- The treatment benefit on rPFS in the ERLEADA group was significant compared with the placebo group in both the high- and low-risk mCSPC subgroups.
- Patients in the ERLEADA group considered high-risk at baseline had significantly improved OS following treatment as well as significantly longer PFS2 compared with the placebo group.

Efficacy Results and First Subsequent Therapies Following Discontinuation for Patients with High- and Low-Risk mCSPC in the TITAN Study¹³

	High-Risk mCSPC		Low-Risk mCSPC
	ERLEADA Group (n=289)	Placebo Group (n=286)	ERLEADA Group (n=236)	Placebo Group (n=241)
rPFS
HR (95% CI; P-value)	0.44 (0.34-0.57; <0.0001)		0.54 (0.38-0.78; 0.001)
OS
24-month survival rate, %	76	63	90	85
HR (95% CI; P-value)	0.62 (0.45-0.87; 0.005)		0.74 (0.44-1.25; 0.261)
PFS2
HR (95% CI; P-value)	0.617 (0.441-0.863; 0.005)		0.693 (0.428-1.124; 0.1351)
	High-Risk mCSPC		Low-Risk mCSPC
	ERLEADA Group (n=107)^a	Placebo Group (n=175)^a	ERLEADA Group (n=63)^a	Placebo Group (n=96)^a
First Subsequent Therapies
Patients with subsequent therapy, n (%)^b	64 (59.8)	126 (72.0)	23 (36.5)	64 (66.7)
Abiraterone acetate plus prednisone	14 (13.1)	31 (17.7)	7 (11.1)	14 (14.6)
Docetaxel	23 (21.5)	45 (25.7)	6 (9.5)	22 (22.9)
Bicalutamide	11 (10.3)	17 (9.7)	5 (7.9)	14 (14.6)
Enzalutamide	2 (1.9)	14 (8.0)	1 (1.6)	3 (3.1)
^aNumber of patients alive at treatment discontinuation. ^bSome patients received subsequent therapies as a result of discontinuation due to AEs.

TEAEs reported in the high- and low-risk subgroups were similar regardless of disease risk and consistent with previously reported results in the overall study population.¹³

Safety Results for Patients With High- and Low-Risk mCSPC in the TITAN Study¹³

AEs, n (%)	High-Risk mCSPC		Low-Risk mCSPC
AEs, n (%)	ERLEADA Group (n=289)^a	Placebo Group (n=286)^b	ERLEADA Group (n=235)^c	Placebo Group (n=241)^d
Patients with TEAEs	278 (96.2)	278 (97.2)	229 (97.4)	231 (95.9)
Patients with serious AEs	62 (21.5)	61 (21.3)	42 (17.9)	46 (19.1)
Drug related	6 (2.1)	2 (0.7)	4 (1.7)	2 (0.8)
Grade 3-4	49 (17.0)	49 (17.1)	35 (14.9)	37 (15.4)
Patients with drug-related TEAEs leading to treatment discontinuation	8 (2.8)	1 (0.3)	9 (3.8)	3 (1.2)
Patients with TEAEs leading to death	7 (2.4)	12 (4.2)	3 (1.3)	4 (1.7)
Drug-related	0	0	0	0
All deaths within 30 days of last dose	13 (4.5)	16 (5.6)	5 (2.1)	7 (2.9)
^a-dMedian treatment duration, months: ^a19.5; ^b14.7; ^c21.8; ^d20.3.

A post hoc analysis evaluated efficacy and safety outcomes for patients with high- and low-volume mCSPC enrolled in the TITAN study.⁷
- Results from the pre-specified analysis evaluating efficacy and safety outcomes in patients with high- and low-volume mCSPC at the primary analysis have previously been reported.⁸
- At the final analysis, the treatment benefit on OS, time to PSA progression, and time to castration resistance observed in the ERLEADA group of the overall study population was additionally improved in the high- and low-volume mCSPC subgroups.⁷
  - Using IPCW log-rank test to account for ~40% crossover, the ERLEADA group had improvement in OS in both high- and low-volume mCSPC (high-volume: HR, 0.61; 95% CI, 0.49-0.78; P<0.0001 and low-volume: HR, 0.34; 95% CI, 0.22-0.53; P<0.0001).
- At 3 months, PSA decline ≥50% (PSA50) and undetectable PSA (≤0.2 ng/mL) in the ERLEADA group was observed in 87% and 40% of patients with high-volume mCSPC and 93% and 68% with low-volume mCSPC, respectively.

Efficacy Results for Patients with High- and Low-Volume mCSPC in the TITAN Study⁷

	High-Volume mCSPC		Low-Volume mCSPC
	ERLEADA Group (n=325)	Placebo Group (n=335)	ERLEADA Group (n=200)	Placebo Group (n=192)
OS
Median, months	NR	38.7	NR	NR
HR (95% CI; P-value)	0.70 (0.56-0.88; 0.002)		0.53 (0.35-0.79; 0.002)
Time to PSA progression
Median, months	NR	9.2	NR	18.5
HR (95% CI; P-value)	0.32 (0.26-0.41; <0.0001)		0.15 (0.09-0.23; <0.0001)
Time to castration resistance
Median, months	NR	8.3	NR	18.5
HR (95% CI; P-value)	0.40 (0.32-0.48; <0.0001)		0.23 (0.16-0.33; <0.0001)

The ERLEADA safety profile in both high- and low-volume mCSPC remained consistent with previous reports.⁷

A protocol-defined and post hoc analysis evaluated efficacy and safety outcomes for patients enrolled in the TITAN study based on disease volume (high vs low), number of metastases (oligometastases vs polymetastases), and timing of metastasis presentation (synchronous vs metachronous).³⁰
- Among patients in the ERLEADA group, those with oligometastatic disease (≤5 bone-only metastases) had improved rPFS and OS compared with those with polymetastatic disease (>5 bone-only metastases, >5 bone metastases plus other organ metastases, or ≤5 bone metastases plus other organ metastases).
  - Patients with polymetastatic disease involving >5 bone metastases plus metastases in other locations had the poorest outcomes.
  - Compared with patients with bone-only metastasis, OS and rPFS were shorter for patients with metastases in bone plus viscera plus other locations (OS: HR, 2.63; 95% CI, 1.68-4.10; P<0.001; rPFS: HR, 3.42; 95% CI, 2.10-5.55; P<0.001) and those with metastases in bone plus other locations (OS: HR, 1.90; 95% CI, 1.37-2.63; P<0.001; rPFS: HR, 2.22; 95% CI, 1.52-3.25; P<0.001)

Primary Efficacy Results in Patients with Different Disease Volume or Timing of Metastasis in the TITAN Study³⁰

	Synchronous/High-Volume mCSPC		Synchronous/Low-Volume mCSPC		Metachronous/High-Volume mCSPC		Metachronous/Low-Volume mCSPC
	ERLEADA (n=273)	Placebo (n=294)	ERLEADA (n=138)	Placebo (n=147)	ERLEADA (n=32)	Placebo (n=28)	ERLEADA (n=53)	Placebo (n=31)
rPFS
Median, months	NR	15.0	NR	32.9	18.7	11.1	NR	NR
HR (95% CI)	0.51 (0.39-0.66)		0.38 (0.22-0.65)		0.57 (0.27-1.24)		0.27 (0.09-0.85)
OS
Median, months	NR	36.7	NR	52.2	NR	39.6	NR	NR
HR (95% CI)	0.68 (0.53-0.87)		0.65 (0.40-1.05)		0.69 (0.33-1.44)		0.22 (0.09-0.55)

PFS2, time to PSA progression, time to castration resistance, select first subsequent life-prolonging therapy for prostate cancer after study treatment discontinuation, and confirmed best ≥50% or ≥90% PSA decline or PSA ≤0.2 ng/mL results were also reported for these patient subgroups.³¹

High-volume mCSPC subgroup TEAEs, grade 3-4 TEAEs, and serious AEs³⁰:
- ERLEADA group: 96%, 54%, and 29% of patients
- Placebo group: 97%, 47%, and 22% of patients
Low-volume mCSPC subgroup TEAEs, grade 3-4 TEAEs, and serious AEs³⁰:
- ERLEADA group: 99%, 43%, and 30% of patients
- Placebo group: 96%, 33%, and 21% of patients
A similar safety profile was observed across treatment groups in the synchronous or metachronous subgroups.³⁰
- One exception was falls and fractures, which were more common in the metachronous subgroup than in the synchronous subgroup.
The cumulative incidence of grade 3-4 TEAEs and serious TEAEs was similar across treatment groups, regardless of disease volume or metastatic status at diagnosis.³⁰

A post hoc analysis evaluated the efficacy, safety, and PROs at the primary and final analyses in older patients, stratified by age (<65, 65-79, and ≥80 years), enrolled in the TITAN study.⁵
- rPFS was analyzed at the first interim analysis, and confirmed deep PSA decline, OS, HRQoL, and safety were analyzed at the final analysis.
- The HR for rPFS favored the ERLEADA vs placebo group for all age subgroups.
- At the final analysis, the HR for OS favored the ERLEADA vs placebo group.

Efficacy Results for Patients by Age Subgroup in the TITAN Study⁵

	<65 Years (n=331)		65-79 Years (n=628)		≥80 Years (n=93)
	ERLEADA Group	Placebo Group	ERLEADA Group	Placebo Group	ERLEADA Group	Placebo Group
rPFS^a
Median, months	NR	18.4	NR	23	NR	NR
HR (95% CI)	0.45 (0.31-0.66)		0.51 (0.39-0.68)		0.55 (0.25-1.21)
OS^b
Median, months	NR	41.7	NR	52.2	NR	41.7
HR (95% CI)	0.57 (0.40-0.80)		0.70 (0.54-0.91)		0.74 (0.40-1.39)
^aMedian follow-up: 22.7 months. ^bMedian follow-up: 44 months.

The treatment effect of ERLEADA on best PSA decline by age group was evaluated using descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards model, and mixed-effects model for repeated measures.

The median (range) treatment duration for patients <65, 65-79, and ≥80 years old in the ERLEADA group was 39.8 (1.0-52.7), 39.8 (0.0-55.7), and 23.6 (2.0-48.2) months, respectively.⁵

At the final analysis, exposure-adjusted rates of TEAEs increased with age regardless of treatment; the rates of TEAEs of interest such as skin rash, falls, and fractures increased with age in the ERLEADA vs placebo group.⁵

Safety Results for Patients by Age Subgroup in the TITAN Study^5,a

	<65 Years (n=330)		65-79 Years (n=628)		≥80 Years (n=93)
	ERLEADA Group (n=148)	Placebo Group (n=182)	ERLEADA Group (n=324)	Placebo Group (n=304)	ERLEADA Group (n=52)	Placebo Group (n=41)
Total exposure, patient-years	386	254	863	481	110	58.7
Exposure-adjusted rate, events/100 patient-years^b
Patients with ≥1 TEAE	329	558	393	504	562	504
Patients with serious TEAEs	11.9	27.5	21.3	18.7	39.9	32.4
TEAEs leading to discontinuation	1.3	2.0	3.9	1.5	10.0	8.5
TEAEs of interest	28.5	20.1	43.3	24.8	58.0	23.9
Skin rash	19.2	10.6	26.4	8.1	27.2	8.5
Fall	2.6	5.5	4.6	7.7	14.5	6.8
Fracture	3.1	2.8	7.0	5.4	10.0	0
Ischemic heart disease	2.6	0	3.6	2.5	4.5	1.7
Ischemic cerebrovascular disorder	0.3	0.4	1.7	1.0	1.8	6.8
Seizure	0.8	0.8	0	0	0	0
^aOne patient did not receive study medication. ^bTEAE rates per 100 patient-years of exposure in each treatment group were calculated as: 100 × distinct events of each preferred term/total patient-year of exposure (total duration of exposure/365.25).

The treatment effect of ERLEADA on HRQoL by age group was evaluated using descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards model, and mixed-effects model for repeated measures. HRQoL was maintained regardless of age and ERLEADA was tolerated well.⁵
- Across age groups, patients receiving ERLEADA or placebo had consistent total FACT-P scores of over 5.4 years.⁵
- Across age groups, per responses from FACT-P physical wellbeing question GP5 (“I am bothered by side effects of treatment”), patients receiving ERLEADA reported either not being bothered by treatment side effects over time or not being any more bothered than patients receiving placebo.⁶
- Across age groups, in patients receiving ERLEADA, overall physical wellbeing and energy levels remained consistent and were comparable with those in patients receiving placebo.⁶
- Per FACT-P total scores, patients aged ≥75 years with a baseline ECOG PS of 1 maintained their general HRQoL.⁵

A post hoc analysis evaluated the efficacy and safety of ERLEADA in patients with D0 or D1 mCSPC at initial diagnosis who were enrolled in the TITAN study.⁹
- At 22.7 months of median follow-up, treatment with ERLEADA (median OS and rPFS, NR) significantly improved OS and rPFS vs placebo (median OS, NR; median rPFS, 22.1 months) in both subgroups.
  - OS, D0: HR, 0.40; 95% CI, 0.15-1.03; P=0.0481 and D1: HR, 0.72; 95% CI, 0.53-0.98; P=0.0339
  - rPFS, D0: HR, 0.41; 95% CI, 0.22-0.77; P=0.0044 and D1: HR, 0.49; 95% CI, 0.39-0.62; P<0.0001
- There was significantly prolonged time to PSA progression in the ERLEADA group compared with the placebo group in both the D0 and D1 subgroups:
  - D0: HR, 0.26; 95% CI, 0.13‑0.50; P<0.0001
  - D1: HR, 0.26; 95% CI, 0.20-0.33; P<0.0001
- In both the D0 and D1 subgroups, treatment in the ERLEADA group increased the percentage of patients with confirmed ≥50% and ≥90% PSA decline, shortened the time to achieve PSA decline, and increased the depth of PSA decline vs the placebo group.⁹

PSA Kinetics in the D0 and D1 Subgroups in the TITAN Study⁹

PSA Kinetics	D0		D1
PSA Kinetics	ERLEADA Group (n=85)	Placebo Group (n=59)	ERLEADA Group (n=411)	Placebo Group (n=441)
Confirmed PSA50, n (%)	76 (89.4)^a	28 (47.5)	370 (90.0)^a	232 (52.4)
Confirmed PSA90, n (%)	57 (67.1)^a	15 (25.4)	302 (73.5)^a	103 (23.4)
Time to PSA50, months, median (range)	n=76 0.95 (0.9-4.6)	n=28 0.97 (0.7-7.4)	n=370 0.95 (0.3-11.1)	n=231 0.95 (0.1-16.6)
Time to PSA90, months, median (range)	n=57 1.84 (0.9-11.0)	n=15 5.59 (0.9-14.8)	n=302 1.87 (0.3-20.3)	n=103 2.76 (0.1-18.4)
Confirmed depth of PSA decline, n (%)
<50%	9 (10.6)	31 (52.5)	41 (10.0)	210 (47.6)
50% to <90%	19 (22.4)	13 (22.0)	68 (16.5)	128 (29.0)
≥90%	57 (67.1)	15 (25.4)	302 (73.5)	103 (23.4)
^aP<0.0001.

The safety results were as follows⁹:

Summary of AEs⁹

AEs, %	D0		D1
AEs, %	ERLEADA Group (n=85)	Placebo Group (n=59)	ERLEADA Group (n=411)	Placebo Group (n=441)
AEs	98.8	96.6	96.4	96.4
AEs leading to treatment discontinuation	11.9	6.8	7.5	5.0
Death within 30 days of treatment dose	2.4	1.7	3.9	4.8

In a post hoc analysis evaluating PFS2 by first subsequent therapy following discontinuation of study treatment in the TITAN study, specifically hormonal compared with taxane therapy, the ERLEADA group demonstrated a reduced risk of PFS2 compared with the placebo group, regardless of hormonal (median, NR in either group; HR, 0.684; 95% CI, 0.482-0.971; P=0.0326) or taxane (median, NR in either group; HR, 0.634; 95% CI, 0.456-0.881; P=0.0062) therapy as the first subsequent therapy.¹⁴
An exploratory analysis evaluated OS beyond the TITAN study follow-up for the overall population, with or without IPCW crossover adjustment, and for the low-volume disease, high-volume disease, high-volume disease synchronous, and high-volume disease metachronous subgroups. Treatment with ERLEADA (median OS, 71.5 months) vs placebo significantly improved OS by a median of 32 months in the overall population. Treatment with ERLEADA improved OS (median OS, 113.1 months) in the low-volume disease subgroup, with a consistent median OS of 52 months across the high-volume disease subgroups.¹⁵
A post hoc analysis of patients in the ERLEADA group showed that rPFS, OS, time to PSA progression, and ≤0.2 ng/mL PSA response were similar among patients who received and those who did not receive prior docetaxel.²⁸
In another analysis that evaluated the pharmacokinetics and relationship between ERLEADA exposure and selected clinical efficacy and safety observations, treatment in the ERLEADA group was found to be efficacious in extending the rPFS and OS compared with the placebo group. No statistical association was observed between rPFS, OS, and ERLEADA exposure quartiles within a relatively narrow ERLEADA exposure range (coefficient of variation, 22%). Patients with increased ERLEADA exposure reported an increased incidence of skin rash and pruritus.²⁹
A descriptive post hoc analysis was conducted to evaluate the incidence of thrombotic and embolic TEAEs in patients who did or did not receive concomitant OACs in the ERLEADA and placebo groups. The occurrence of thrombotic and embolic TEAEs was similar between the ERLEADA and placebo groups in the overall safety population (4.2% vs 3.8%) and in the subgroups that did (19.4% vs 21.4%) or did not (3.2% vs 2.8%) receive anticoagulants, respectively.²⁶
Additional analyses evaluating the effect of prior prostate-directed local therapy on ERLEADA therapy response, association between PSA progression and radiographic progression, molecular signatures, subtypes, and androgen receptor activity and aberrations with long-term outcomes have been reported.^16-22 There have additionally been patient subgroup analyses conducted for Latin American, Japanese, and East Asian patients enrolled in the TITAN study.^23-25

ADT	Androgen deprivation therapy	MedDRA	Medical Dictionary for Regulatory Activities
AE	Adverse event	MI	Myocardial infarction
ALP	Alkaline phosphatase	MRI	Magnetic resonance imaging
BFI	Brief Fatigue Inventory	NCI CTCAE	National Cancer Institute Common Terminology Criteria for Adverse Events
BPI-SF	Brief Pain Inventory-Short Form	NE	Not estimable
CI	Confidence interval	NR	Not reached
COVID-19	Coronavirus Disease 2019	OAC	Oral anticoagulant
CRPC	Castration-resistant prostate cancer	OS	Overall survival
CT	Computed tomography	PCWG2	Prostate Cancer Working Group 2
D0	Progression to mCSPC after localized disease	PFS2	Second progression-free survival
D1	De novo mCSPC	PO	Orally
ECOG PS	Eastern Cooperative Oncology Group Performance Status	PRO	Patient-reported outcome
EuroQoL EQ-5D-5L	5-level version of the European Quality of Life-5 Dimensions	PSA	Prostate-specific antigen
FACT-P	Functional Assessment of Cancer Therapy-Prostate	PSA50	PSA decline of ≥50%
GnRH	Gonadotropin-releasing hormone	PSA90	PSA decline of ≥90%
HR	Hazard ratio	RECIST	Response Evaluation Criteria In Solid Tumors
HRQoL	Health-related quality of life	rPFS	Radiographic progression-free survival
IDMC	Independent data-monitoring committee	SMQ	Standardized MedDRA Query
IPCW	Inverse probability censoring weighted	TEAE	Treatment-emergent adverse event
mCSPC	Metastatic castration-sensitive prostate cancer	TTD	Time to deterioration

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 18 September 2024.

Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
Chi KN, Agarwal N, Bjartell A, et al. Protocol for: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303.
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Shen J, Chowdhury S, Agarwal N, et al. Supplement for: Apalutamide efficacy, safety and wellbeing in older patients with advanced prostate cancer from phase 3 randomised clinical studies TITAN and SPARTAN. Br J Cancer. 2024;130(1):73-81.
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Uemura H, Ha Chung B, Ye D, et al. Apalutamide for metastatic castration-sensitive prostate cancer in TITAN: outcomes in patients with high- and low-volume disease. Oral presentation presented at: Japan Society of Clinical Oncology (JSCO) Annual Meeting; October 24-26, 2019; Fukuoka, Japan.
Bjartell A, Ye D, Agarwal N, et al. Apalutamide plus androgen deprivation therapy for metastatic castration-sensitive prostate cancer (mCSPC) in TITAN: outcomes in patients with de novo (D1) mCSPC vs progression to mCSPC after localized disease (D0) at diagnosis. Poster presented at: 35th Annual European Association of Urology (EAU) Congress Virtual Meeting; July 17-26, 2020.
Chowdhury S, Bjartell A, Agarwal N, et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol. 2023;34(5):477-485.
Chi KN, Saad F, Chowdhury S, et al. Prostate-specific antigen kinetics in patients with advanced prostate cancer treated with apalutamide: results from the TITAN and SPARTAN studies. Poster presented at: American Society of Clinical Oncology (ASCO) 20 Virtual Scientific Program; May 29-31, 2020.
Chi KN, Saad F, Chowdhury S, et al. Prostate-specific antigen kinetics in patients with advanced prostate cancer treated with apalutamide: results from the TITAN and SPARTAN studies. Oral presentation presented at: The 2021 American Urological Association (AUA) Annual Meeting; September 10-13, 2021; Virtual Meeting.
Ozguroglu M, Chowdhury S, Bjartell A, et al. Apalutamide for metastatic castration-sensitive prostate cancer in TITAN: outcomes in patients with low- and high-risk disease. Poster presented at: 2020 Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA.
Agarwal N, Chowdhury S, Bjartell A, et al. Time to second progression (PFS2) in patients from TITAN with metastatic castration-sensitive prostate cancer by first subsequent therapy (hormonal vs taxane). Oral presentation presented at: 2020 Genitourinary Cancers Symposium; February 13-15, 2020; San Francisco, CA.
Agarwal N, Bjartell A, Juárez A, et al. Estimating median overall survival of apalutamide compared with placebo in metastatic hormone-sensitive prostate cancer (mHSPC) populations: statistical extrapolations of the TITAN study. Poster presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; January 25-27, 2024; San Francisco, CA.
Roy S, Saad F, Malone S, et al. Effect of prior prostate directed local therapy on response to apalutamide in metastatic hormone sensitive prostate cancer: a secondary analysis of the TITAN study. Eur Urol. 2024;85(4):398-400.
Fukuokaya W, Yanagisawa T, Mori K, et al. Radiographic progression without corresponding prostate-specific antigen progression in patients with metastatic castration-sensitive prostate cancer receiving apalutamide: secondary analysis of the TITAN trial. [published online ahead of print April 29, 2024]. Eur Urol Oncol. doi: 10.1016/j.euo.2024.04.009.

Bjartell A, Agarwal N, Karsh LI, et al. Relationships of sites and burden of metastases with long-term outcomes and molecular subtypes in TITAN. Poster presented at: The 2021 American Urological Association (AUA) Annual Meeting; September 10-13, 2021; Virtual Meeting.
Feng FY, Thomas S, Aguilar-Bonavides C, et al. Molecular determinants of outcome for metastatic castration-sensitive prostate cancer with addition of apalutamide or placebo to androgen deprivation therapy in TITAN. Poster presented at: American Society of Clinical Oncology (ASCO) 20 Virtual Scientific Program; May 29-31, 2020.
Lucas J, Agarwal N, Feng F, et al. Molecular signatures associated with long-term response to apalutamide in patients with metastatic castration-sensitive prostate cancer in TITAN. Poster presented at: American Association for Cancer Research (AACR) 2021 Virtual Meeting; April 10-15, 2021.
Chi KN, Thomas S, Gormley M, et al. Androgen receptor and non-androgen receptor aberrations associated with outcomes in metastatic castration-sensitive prostate cancer treated with apalutamide plus androgen deprivation therapy in TITAN. Poster presented at: American Association for Cancer Research (AACR) 2020 Virtual Meeting II; June 22-24, 2020.
Agarwal N, Lucas J, Bonavides CA, et al. Genomic aberrations associated with overall survival (OS) in metastatic castration-sensitive prostate cancer (mCSPC) treated with apalutamide (APA) or placebo (PBO) plus androgen deprivation therapy (ADT) in TITAN. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL and online.
Juarez A, Chi KN, Pereira AJ, et al. Latin american patient subgroup analysis of the phase 3 TITAN study: apalutamide plus ADT in metastatic hormone-sensitive prostate cancer (mHSPC). Poster presented at: American Association for Cancer Research (AACR) 2021 Virtual Meeting; April 10-15, 2021.
Uemura H, Arai G, Uemura H, et al. Safety and efficacy of apalutamide in Japanese patients with metastatic castration- sensitive prostate cancer receiving androgen deprivation therapy: Final report for the Japanese subpopulation analysis of the randomized, placebo-controlled, phase III TITAN study. Int J Urol. 2022;29(6):533-540.
Chung BH, Huang J, Uemura H, et al. Apalutamide for metastatic castration-sensitive prostate cancer: final analysis of the Asian subpopulation in the TITAN trial. Asian J Androl. 2023;25(6):653-661.
Potdar R, Gartrell BA, Given R, et al. Concomitant use of oral anticoagulants in patients with advanced prostate cancer receiving apalutamide: A post-hoc analysis of TITAN and SPARTAN studies. Am J Cancer Res. 2022;12(1):445-450.
Small EJ, Chi KN, Chowdhury S, et al. Post hoc analysis of rapid and deep prostate-specific antigen decline and patient-reported health-related quality of life in SPARTAN and TITAN patients with advanced prostate cancer. Eur Urol Oncol. 2024;7(4):844-852.
Chi KN, Merseburger AS, Ozguroglu M, et al. The effect of prior docetaxel treatment on efficacy and safety of apalutamide plus androgen deprivation therapy in patients with metastatic castration-sensitive prostate cancer from TITAN. Poster presented at: 2022 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, CA.
T'jollyn H, Ackaert O, Chien C, et al. Efficacy and safety exposure-response relationships of apalutamide in patients with metastatic castration-sensitive prostate cancer: results from the phase 3 TITAN study. Cancer Chemother Pharmacol. 2022;89(5):629-641.
Merseburger AS, Agarwal N, Bhaumik A, et al. Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: a subgroup analysis of the randomised clinical TITAN study. Eur J Cancer. 2023;193:113290.
Merseburger AS, Agarwal N, Bhaumik A, et al. Supplement to: Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: a subgroup analysis of the randomised clinical TITAN study. Eur J Cancer. 2023;193:113290.
Merseburger AS, Agarwal N, Bjartell A, et al. Effect of rapid ultra-low prostate-specific antigen decline in TITAN patients with metastatic castration-sensitive prostate cancer who received apalutamide plus androgen deprivation therapy. Poster presented at: 2023 European Society for Medical Oncology (ESMO); October 20-24, 2023; Madrid, Spain.
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Chi KN, Agarwal N, Bjartell A, et al. Supplement to: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24.
Agarwal N, McQuarrie K, Bjartell A, et al. Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2019;20(11):1518-1530.
Agarwal N, McQuarrie K, Bjartell A, et al. Apalutamide plus androgen deprivation therapy for metastatic castration-sensitive prostate cancer: analysis of pain and fatigue in the phase 3 TITAN study. J Urol. 2021;206(4):914-923.
Agarwal N, Chowdhury S, Bjartell A, et al. Health-related quality of life and patient-reported outcomes at final analysis of the TITAN study of apalutamide vs placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy. Poster presented at: 2021 American Society of Clinical Oncology (ASCO) Annual Meeting; June 4-8, 2021; Virtual Meeting.

Last updated: 07 October 2024

	ERLEADA Group (n=525)	Placebo Group (n=527)
Gleason score at initial diagnosis, n (%)
<7	41 (7.8)	39 (7.4)
7	133 (25.3)	130 (24.7)
>7	351 (66.9)	358 (67.9)
Metastatic stage at initial diagnosis, n (%)
M0 (negative)	85 (16.2)	59 (11.2)
M1 (positive)	411 (78.3)	441 (83.7)
MX (unknown)	29 (5.5)	27 (5.1)
Disease volume, n (%)
Low	200 (38.1)	192 (36.4)
High	325 (61.9)	335 (63.6)
Extent of disease at study entry, n (%)
Bone	525 (100.0)	527 (100.0)
Bone only	289 (55.0)	269 (51.0)
Lymph node	199 (37.9)	219 (41.6)
Visceral and bone	56 (10.7)	72 (13.7)
Lung	47 (9.0)	64 (12.1)
Liver	12 (2.3)	13 (2.5)
Soft tissue and bone	22 (4.2)	27 (5.1)
Prior docetaxel,^a n (%)	58 (11.0)	55 (10.4)
Prior therapy for localized prostate cancer, n (%)
Prostatectomy or radiotherapy	94 (17.9)	79 (15.0)
Prostatectomy only	26 (5.0)	27 (5.1)
Radiotherapy only	47 (9.0)	39 (7.4)
Both prostatectomy and radiotherapy	21 (4.0)	13 (2.5)
Prior hormonal therapy for prostate cancer, n (%)	525 (100.0)	527 (100.0)
First-generation antiandrogen	352 (67.0)	361 (68.5)
GnRH agonist	462 (88.2)	455 (86.3)
GnRH antagonist	56 (10.7)	53 (10.1)
Bilateral orchiectomy	33 (6.3)	40 (7.6)
Median PSA, μg/L (range)	5.97 (0-2682)	4.02 (0-2229)

^aA total of 27 (46.6%) and 22 (40.0%) patients in the ERLEADA and placebo groups, respectively, had lymph node-positive disease (N1) at diagnosis. Both groups received a median of 6 cycles of docetaxel treatment.

PSA, prostate-specific antigen.

Endpoints	ERLEADA Group (n=525)	Placebo Group (n=527)	Hazard Ratio (95% CI)	P-Value
Dual Primary Endpoints
Median rPFS, months	NE	22.1	0.48 (0.39-0.60)	<0.001
Median OS, months	NE	NE	0.67 (0.51-0.89)	0.005
Secondary Endpoints
Median time to cytotoxic chemotherapy, months	NE	NE	0.39 (0.27-0.56)	<0.001
Median time to pain progression,^a months	NE	NE	0.83 (0.65-1.05)	0.12^b
Median time to chronic opioid use, months	NE	NE	0.77 (0.54-1.11)	-
Median time to skeletal-related events,^c months	NE	NE	0.80 (0.56-1.15)	-
Exploratory Endpoints
Median time to symptomatic local progression, months	NE	NE	1.20 (0.71-2.02)	-
Median time to PSA progression, months	NE	12.9	0.26 (0.21-0.32)	-
Median PFS2, months	NE	NE	0.66 (0.50-0.87)	-

^aPain progression was reported by patients using BPI-SF item 3 (worst pain). Scores range from 0 to 10, with lower scores representing lower levels of pain intensity; a change of 2 was the minimally important difference.
^bSecondary endpoints were tested in a preplanned hierarchical sequence. When time to pain progression was determined not to be significantly improved with ERLEADA, further secondary endpoints were not formally tested.
^cSkeletal-related events were defined as the occurrence of symptomatic pathological fracture, spinal cord compression, radiation to bone, or surgery to bone.

Based on results from this first planned interim analysis, the IDMC recommended unblinding to allow a crossover of patients receiving placebo to receive ERLEADA.¹

CI, confidence interval; IDMC, independent data-monitoring committee; NE, not estimable; OS, overall survival; PFS2, second progression-free survival; PSA, prostate-specific antigen; rPFS, radiographic progression-free survival.

Endpoint	ERLEADA Group (n=525)	Placebo Group (n=527)	Hazard Ratio (95% CI)	P-Value
Dual Primary Endpoint
Median OS, months	NR	52.2	0.65 (0.53-0.79)	<0.0001
Secondary Endpoints
Median time to initiation of cytotoxic chemotherapy,^b months	NR	NR	0.47 (0.35-0.63)	Nominal P<0.0001^c
Median time to pain progression, months	NR	NR	0.87 (0.70-1.08)	Nominal P=0.197^c
Median time to chronic opioid use, months	NR	NR	0.79 (0.58-1.09)	Nominal P=0.156^c
Median time to skeletal-related event, months	NR	NR	0.86 (0.62-1.19)	Nominal P=0.361^c
Exploratory Endpoints
Median time to PSA progression,^d months	NR	12.9	0.27 (0.22-0.33)	Nominal P<0.0001^c
Median PFS2,^e months	NR	44.0	0.62 (0.51-0.75)	Nominal P<0.0001^c
Ad Hoc Endpoint
Median time to castration resistance,^f months	NR	11.4	0.34 (0.29-0.41)	Nominal P<0.0001^c

^aOS results did not include formal statistical inference and the updated analyses presented for secondary endpoints were based on the final data cutoff and performed without formal statistical retesting. The final formal statistical testing for all secondary endpoints was performed at the time of the first interim analysis.
^b69 patients in the ERLEADA group and 126 patients in the placebo group initiated cytotoxic chemotherapy.
^cThese endpoints were not adjusted for multiple comparisons. Therefore, the P-values displayed are nominal, and statistical significance has not been established.
^d138 patients in the ERLEADA group and 344 patients in the placebo group experienced PSA progression.
^e173 patients in the ERLEADA group and 246 patients in the placebo group experienced progression on or after first subsequent therapy or death.
^f191 patients in the ERLEADA group and 375 patients in the placebo group developed castration-resistant prostate cancer.

CI, confidence interval; NR, not reached; OS, overall survival; PFS2, second progression-free survival; PSA, prostate-specific antigen.

AE, n (%)	ERLEADA Group (n=524)		Placebo Group (n=527)
AE, n (%)	Any Grade	Grade 3-4	Any Grade	Grade 3-4
Rash	142 (27.1)	33 (6.3)	45 (8.5)	3 (0.6)
Fall	39 (7.4)	4 (0.8)	37 (7.0)	4 (0.8)
Fracture	33 (6.3)	7 (1.3)	24 (4.6)	4 (0.8)
Hypothyroidism	34 (6.5)	0	6 (1.1)	0
Seizure	3 (0.6)	1 (0.2)	2 (0.4)	0

AE, adverse event.

AE,^a n (%)	ERLEADA Group (n=524)		Placebo Group (n=527)		Crossover Group (n=208)
AE,^a n (%)	All Grades	Grade ≥3	All Grades	Grade ≥3	All Grades	Grade ≥3
Treatment-related TEAEs occurring in ≥5% of patients^b
Patients with ≥1 treatment-related TEAE	319 (60.9)	-	221 (41.9)	-	93 (44.7)	-
Rash	92 (17.6)	-	12 (2.3)	-	23 (11.1)	-
Pruritus	43 (8.2)	-	13 (2.5)	-	8 (3.8)	-
Fatigue	71 (13.5)	-	46 (8.7)	-	14 (6.7)	-
Hot flush	67 (12.8)	-	52 (9.9)	-	3 (1.4)	-
Hypertension	28 (5.3)	-	21 (4.0)	-	5 (2.4)	-
AEs of interest, by group term^c,d
Skin rash	153 (29.2)	33 (6.3)	49 (9.3)	5 (0.9)	45 (21.6)	8 (3.8)
Fracture	54 (10.3)	18 (3.4)	26 (4.9)	4 (0.8)	5 (2.4)	0
Fall	49 (9.4)	7 (1.3)	37 (7.0)	5 (0.9)	8 (3.8)	0
Ischemic heart disease	31 (5.9)	16 (3.1)	11 (2.1)	4 (0.8)	1 (0.5)	1 (0.5)
Ischemic cerebrovascular disorder	13 (2.5)	8 (1.6)	8 (1.5)	1 (0.2)	5 (2.4)	5 (2.4)
Seizure	3 (0.6)	1 (0.2)	2 (0.4)	0	0	0

^aShown are AEs of any cause, unless otherwise noted, that occurred from the time of the first dose of the trial intervention through 30 days after the last dose. For each category, patients with multiple events were counted only once. AEs were assessed monthly and graded according to NCI CTCAE, version 4.0.3. One patient who was assigned to the ERLEADA group withdrew consent before treatment.
^bExcludes grade 5 events.
^cThe worst toxicity grade was included. Patients with missing toxicity grade were counted in the all-grade column.
^dThe incidences of the following TEAEs (all grade) were adjusted for exposure (event rate per 100 patient-years of exposure) in the ERLEADA, placebo, and crossover groups, respectively: skin rash (331 [24.4%] vs 66 [8.3%] vs 44 [18.1%]), fracture (83 [6.1%] vs 33 [4.2%] vs 5 [2.1%]), fall (63 [4.6%] vs 54 [6.8%] vs 14 [5.7%]), ischemic heart disease (45 [3.3%] vs 13 [1.6%] vs 1 [0.4%]), ischemic cerebrovascular disorders (18 [1.3%] vs 10 [1.3%] vs 7 [2.9%]), and seizure (3 [0.2%] vs 2 [0.3%] vs 0).

AE, adverse event; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; TEAE, treatment- emergent adverse event.

	<65 Years (n=331)		65-79 Years (n=628)		≥80 Years (n=93)
	ERLEADA Group	Placebo Group	ERLEADA Group	Placebo Group	ERLEADA Group	Placebo Group
Median (range) PSA nadir,^a ng/mL	0.04 (0-133) n=148	0.93 (0-408) n=181	0.02 (0-498) n=321	0.68 (0-1408) n=303	0.04 (0-83.7) n=52	0.73 (0-1180) n=41
Median time (range) to PSA nadir,^a months	5.6 (0.1-40.6) n=149	2.8 (0.7-50.6) n=182	5.6 (0.1-47.9) n=324	4.7 (0.8-50.0) n=304	6.4 (1.0-36.8) n=52	3.7 (0.7-40.4) n=41
Confirmed PSA decline ≥50% from baseline,^b n (%)	132 (89) n=149	86 (47) n=182	292 (90) n=324	180 (59) n=304	49 (94) n=52	24 (59) n=41
Median time (range) to confirmed PSA decline ≥50% from baseline,^b,c months	0.95 (0.9-8.3) n=149	0.97 (0.1-30.7) n=182	0.95 (0.3-11.1) n=324	0.99 (0.1-35.4) n=304	0.95 (0.9-9.2) n=52	1.4 (0.9-23.5) n=41
Confimed PSA decline to ≤0.2 ng/mL,^b n (%)	90 (60) n=149	52 (29) n=182	231 (71) n=324	101 (33) n=304	35 (67) n=52	13 (32) n=41
Median time (range) to confirmed PSA decline of ≤0.2 ng/mL,^b,d months	1.9 (0.9-29.4) n=149	1.0 (0.8-39.6) n=182	1.9 (0.1-33.2) n=324	2.8 (0.7-42.0) n=304	1.9 (0.9-25.8) n=52	4.7 (0.9-33.1) n=41

^aPatients with available PSA data are included.
^bConfirmed by a subsequent measurement ≥4 weeks later.
^cAssessed in patients with achieved ≥50% PSA decline from baseline.
^dAssessed in patients with achieved PSA decline to ≤0.2 ng/mL.

PSA, prostate-specific antigen.

n (%)	<65 Years (n=330)		65-79 Years (n=628)		≥80 Years (n=93)
n (%)	ERLEADA Group (n=148)	Placebo Group (n=182)	ERLEADA Group (n=324)	Placebo Group (n=304)	ERLEADA Group (n=52)	Placebo Group (n=41)
Patients with ≥1 TEAE^b,c	142 (96)	177 (97)	316 (98)	292 (96)	52 (100)	41 (100)
Grade 3–4 TEAEs	70 (47)	82 (45)	155 (48)	114 (38)	34 (65)	24 (59)
Patients with serious TEAEs^b	33 (22)	41 (23)	95 (29)	63 (21)	25 (48)	11 (27)
TEAEs leading to treatment discontinuation	7 (4.7)	6 (3.3)	42 (13)	18 (5.9)	13 (25)	6 (15)
TEAEs leading to death	2 (1.4)	2 (1.1)	16 (4.9)	14 (4.6)	2 (3.8)	1 (2.4)
≥1 TEAE of interest	47 (32)	26 (14)	149 (46)	64 (21)	26 (50)	9 (22)
Skin rash	31 (21)	18 (9.9)	103 (32)	28 (9.2)	19 (37)	3 (7.3)
Fall	7 (4.7)	9 (4.9)	33 (10)	25 (8.2)	9 (17)	3 (7.3)
Fracture	9 (6.1)	7 (3.8)	38 (12)	19 (6.3)	7 (14)	0
Ischemic heart disease	5 (3.4)	0	22 (6.8)	10 (3.3)	4 (7.7)	1 (2.4)
Ischemic cerebrovascular disorder	1 (0.7)	1 (0.5)	10 (3.1)	5 (1.6)	2 (3.8)	2 (4.9)
Seizure	3 (2.0)	2 (1.1)	0	0	0	0

^aOne patient did not receive study medication.
^bPatients were counted only once in each category, even if they experienced multiple events in that category.
^cExcluding grade 5 events.

TEAE, treatment-emergent adverse event.

ERLEADA® (apalutamide)

Medical Information

ERLEADA® - TITAN Study

Overview¹

Key Eligibility Criteria¹

Study Design^1,2

Efficacy Results^1,3

Safety Results^3,4

Additional Analyses^5-33

Dual Primary Endpoints¹

Secondary Endpoints^1,34

Exploratory Endpoints^1,28,36

Ad Hoc Endpoint⁴

Secondary Objective¹

Select Baseline Patient and Disease Characteristics^1,34

Summary of AEs^1,34

Summary of AEs^3,4

PSA Relationship to rPFS and OS

PSA Relationship to HRQoL

Effect of Ultra-Low PSA on Clinical Outcomes

Early PSA Response

Efficacy Results and First Subsequent Therapies Following Discontinuation for Patients with High- and Low-Risk mCSPC in the TITAN Study¹³

Safety Results for Patients With High- and Low-Risk mCSPC in the TITAN Study¹³

Efficacy Results for Patients with High- and Low-Volume mCSPC in the TITAN Study⁷

Primary Efficacy Results in Patients with Different Disease Volume or Timing of Metastasis in the TITAN Study³⁰

Efficacy Results for Patients by Age Subgroup in the TITAN Study⁵

Safety Results for Patients by Age Subgroup in the TITAN Study^5,a

PSA Kinetics in the D0 and D1 Subgroups in the TITAN Study⁹

Summary of AEs⁹

Medical inquiries

ERLEADA® (apalutamide)

Medical Information

ERLEADA® - TITAN Study

Overview1

Key Eligibility Criteria1

Study Design1,2

Efficacy Results1,3

Safety Results3,4

Additional Analyses5-33

Dual Primary Endpoints1

Secondary Endpoints1,34

Exploratory Endpoints1,28,36

Ad Hoc Endpoint4

Secondary Objective1

Select Baseline Patient and Disease Characteristics1,34

Additional Baseline Patient and Disease Characteristics

Prespecified Primary, Secondary, and Exploratory Endpoints

Other Exploratory Endpoints

Primary, Secondary, and Additional Endpoints

Summary of AEs1,34

AEs of Special Interest

Summary of AEs3,4

Treatment-Related TEAEs and AEs of Interest

PSA Relationship to rPFS and OS

PSA Relationship to HRQoL

Effect of Ultra-Low PSA on Clinical Outcomes

Early PSA Response

Efficacy Results and First Subsequent Therapies Following Discontinuation for Patients with High- and Low-Risk mCSPC in the TITAN Study13

Safety Results for Patients With High- and Low-Risk mCSPC in the TITAN Study13

Efficacy Results for Patients with High- and Low-Volume mCSPC in the TITAN Study7

Primary Efficacy Results in Patients with Different Disease Volume or Timing of Metastasis in the TITAN Study30

Efficacy Results for Patients by Age Subgroup in the TITAN Study5

PSA Kinetics by Age

Summary of TEAEs

Safety Results for Patients by Age Subgroup in the TITAN Study5,a

PSA Kinetics in the D0 and D1 Subgroups in the TITAN Study9

Summary of AEs9

Medical inquiries

Overview¹

Key Eligibility Criteria¹

Study Design^1,2

Efficacy Results^1,3

Safety Results^3,4

Additional Analyses^5-33

Dual Primary Endpoints¹

Secondary Endpoints^1,34

Exploratory Endpoints^1,28,36

Ad Hoc Endpoint⁴

Secondary Objective¹

Select Baseline Patient and Disease Characteristics^1,34

Summary of AEs^1,34

Summary of AEs^3,4

Efficacy Results and First Subsequent Therapies Following Discontinuation for Patients with High- and Low-Risk mCSPC in the TITAN Study¹³

Safety Results for Patients With High- and Low-Risk mCSPC in the TITAN Study¹³

Efficacy Results for Patients with High- and Low-Volume mCSPC in the TITAN Study⁷

Primary Efficacy Results in Patients with Different Disease Volume or Timing of Metastasis in the TITAN Study³⁰

Efficacy Results for Patients by Age Subgroup in the TITAN Study⁵

Safety Results for Patients by Age Subgroup in the TITAN Study^5,a

PSA Kinetics in the D0 and D1 Subgroups in the TITAN Study⁹

Summary of AEs⁹