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ERLEADA® (apalutamide)

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ERLEADA - Second Progression-Free Survival (PFS2)

Last Updated: 04/04/2024

SUMMARY

In SPARTAN, the phase 3 study that evaluated the efficacy and safety of ERLEADA plus androgen deprivation therapy (ADT) compared to placebo plus ADT in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC; N=1207), the exploratory endpoint of PFS2 was longer in the ERLEADA group compared to the placebo group (median PFS2 not reached [NR] in the ERLEADA group vs 39 months in the placebo group; HR, 0.49; 95% CI, 0.36-0.66) at the primary analysis.¹
- At the final analysis (following 428 events) for overall survival (OS), after a median follow-up of 52 months, the median PFS2 was 55.6 months and 41.2 months in the ERLEADA group and placebo group, respectively (HR, 0.55; 95% CI, 0.46-0.66; nominal P<0.0001).² This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
- PFS2 results were also previously reported in the second interim analysis for OS.³
In TITAN, the phase 3 study that evaluated the efficacy and safety of ERLEADA plus ADT compared to placebo plus ADT in patients with metastatic castration-sensitive prostate cancer (mCSPC; N=1052), the exploratory endpoint of PFS2 was longer in the ERLEADA group compared to the placebo group (median PFS2 not able to be estimated in both groups; HR, 0.66; 95% CI, 0.50–0.87) at the primary analysis. The 24-month event-free rates for PFS2 were 81% and 72% in the ERLEADA and placebo groups, respectively.⁴^,⁵
- At the final analysis (following 405 deaths) for OS, after a median follow-up of 44.0 months, the median PFS2 was NR in the ERLEADA group and 44 months in the placebo group (HR, 0.62; 95% CI, 0.51-0.75; nominal P<0.0001). This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.⁶
- Additional analyses evaluated PFS2 by first subsequent therapy (specifically hormonal vs taxane therapy) after treatment discontinuation⁷, PFS2 in patients with baseline high- and low-risk disease⁸, and PFS2 in patients with high/low-volume, synchronous/metachronous, and oligometastatic/polymetastatic disease.⁹
Additional analyses of PFS2 in the SPARTAN and TITAN studies have been conducted.¹⁰^-¹⁶

CLINICAL DATA

SPARTAN Study

SPARTAN (NCT01946204) was the phase 3, randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of ERLEADA plus ADT compared to placebo plus ADT in patients with high-risk nmCRPC (N=1207).¹ Patients were required to have confirmation of non-metastatic disease by blinded independent central review (BICR). Patients were randomized 2:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=806) or placebo once daily (n=401). All patients received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy.

PFS2, defined as time from randomization to investigator-assessed disease progression (PSA progression, detection of metastatic disease on imaging, symptomatic progression, or any combination) during the first subsequent treatment for metastatic castration-resistant prostate cancer (mCRPC) or death from any cause, was an exploratory endpoint (Figure: SPARTAN Study Design).¹⁷

After the first detection of distant metastasis, patients were eligible to receive sponsorprovided abiraterone acetate plus prednisone as a treatment option. All poststudy treatment for mCRPC was at the treating physician’s discretion.¹⁷

SPARTAN Study Design¹^,¹⁷^,¹⁸

Abbreviations: 99mTc, technetium-99m; ADT, androgen deprivation therapy; CT, computed tomography; GnRH, gonadotropin-releasing hormone; mCRPC, metastatic castration-resistant prostate cancer; MFS, metastasis-free survival; nmCRPC, non-metastatic castration-resistant prostate cancer; PFS2, second progression-free survival; PSADT, prostate-specific antigen doubling time; R, randomization; rPFS, radiographic progression-free survival.
^aContinuous ADT with a GnRH analog or surgical castration was required for patients in both treatment arms in order to maintain castrate levels of testosterone (<50 ng/dL); choice of medical castration was at the discretion of the investigator.
^bAfter the first detection of distant metastasis, patients were eligible to receive sponsor-provided abiraterone acetate plus prednisone as a treatment option. After the trial regimen was discontinued, all post-study treatment for mCRPC was at the treating physician’s discretion.

Results

Patient Characteristics

Patient demographic and disease characteristics were well balanced between the 2 groups, and there were no significant differences.
At the clinical cutoff date for the primary analysis, driven by metastasis events or death, the median follow-up was 20.3 months, with 60.9% of patients still on treatment in the ERLEADA group vs 29.9% in the placebo group.

Efficacy

Primary Analysis

At the final analysis for metastasis-free survival (MFS) performed after 378 events of distant metastasis or death (184 [22.8%] patients in the ERLEADA group and 194 [48.4%] patients in the placebo group), significant improvement in median MFS was observed: 40.5 months vs 16.2 months in the ERLEADA group vs the placebo group, respectively (HR, 0.28; 95% CI, 0.23-0.35; P<0.001).
ERLEADA was associated with improvements in all secondary endpoints, with significant improvement observed in time to metastasis, progression-free survival (PFS), and time to symptomatic progression (all P<0.001), as well as improvements in the exploratory endpoint of PFS2.
Based on the efficacy and safety data, the independent data and safety monitoring committee (IDMC) unanimously recommended unblinding the study and offering patients assigned to the placebo group the option to receive ERLEADA.
- After unblinding of the study, 76 (19%) of patients in the placebo group received therapy with ERLEADA plus ADT (crossover group).²

PFS2 and Subsequent Treatments – Primary Analysis

PFS2 was longer in the ERLEADA group in comparison to the placebo group (HR, 0.49; 95% CI, 0.36-0.66). The median PFS2 was NR in the ERLEADA group compared to a median PFS2 of 39 months in the placebo group.
Of the patients that discontinued study treatment, 52.5% of ERLEADA-treated patients and 77.8% of placebo-treated patients received subsequent approved treatment for mCRPC (Table: First Subsequent Systemic Prostate Cancer Therapy).
- The most common subsequent treatment was abiraterone acetate plus prednisone (75.8% in the ERLEADA group and 74.2% in the placebo group), which was offered as a sponsor-provided treatment option for patients after the first detection of distant metastasis.
- Median time from detection of distant metastasis to initiation of subsequent therapy was 56 days vs 44 days in the ERLEADA group vs the placebo group, respectively.

Final OS Analysis

The median treatment duration was 32.9 months in the ERLEADA group, 11.5 months in the placebo group, and 26.1 months in the crossover group.²
At the final analysis for OS performed (following 428 events; 274 patients in the ERLEADA group and 154 patients in the placebo group) after a median follow-up of 52 months, a statistically significant improvement in median OS was observed: 73.9 months vs 59.9 months in the ERLEADA group vs the placebo group, respectively (HR, 0.78; 95% CI, 0.64-0.96; P=0.016).²
Thirty percent of patients in the ERLEADA group and 61% of patients in the crossover group continued treatment with ERLEADA plus ADT.²

PFS2 and Subsequent Treatments – Updated Analysis

Of the 401 patients randomized to the placebo group, 338 (84%) patients received either life-prolonging active therapy as the first subsequent therapy upon disease progression or ERLEADA as a crossover therapy option without progression after study unblinding.²
The median PFS2 in the ERLEADA group was 55.6 months and 41.2 months in the placebo group (HR, 0.55; 95% CI, 0.46-0.66; nominal P<0.0001). This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.²
There were 319 patients in the ERLEADA group and 190 patients in the placebo group that experienced progression on or after first subsequent therapy or death.²
A total of 48% of ERLEADA-treated patients and 71% of placebo-treated patients received first subsequent systemic therapy for prostate cancer, with abiraterone acetate plus prednisone as the most common first subsequent therapy (Table: First Subsequent Systemic Prostate Cancer Therapy).²^,¹⁹

First Subsequent Systemic Prostate Cancer Therapy¹⁹^,²⁰

Primary Analysis	ERLEADA Group (n=803)^a	Placebo Group (n=398)^a
Discontinued study treatment, n	314	279
Discontinued due to disease progression, n (%)	155 (19.3)	210 (52.8)
Received approved therapy for mCRPC, n (%)	165 (52.5)	217 (77.8)
First subsequent approved treatment,^b n
Abiraterone acetate plus prednisone	125	161
Enzalutamide	20	28
Docetaxel	15	18
Cabazitaxel	0	1
Sipuleucel-T	4	9
Radium-223	1	0
Updated Analysis
n (%)	(n=803)^c	(n=322)^c
Discontinued study treatment	566 (70)	322 (100)
Discontinued due to disease progression	343 (43)	238 (74)
n (%)	(n=806)	(n=401)
Received first subsequent systemic therapy for prostate cancer	386 (48)	285 (71)
First subsequent therapy
Abiraterone acetate plus prednisone	282 (73)	206 (72)
Enzalutamide	32 (8.3)	38 (13)
Docetaxel	33 (8.5)	20 (7.0)
Carboplatin	4 (1.0)	0
Radium-223	2 (0.5)	1 (0.4)
Sipuleucel-T	9 (2.3)	8 (2.8)
Other^d	24 (6.2)	12 (4.2)
Abbreviations: ADT, androgen deprivation therapy; mCRPC, metastatic castration-resistant prostate cancer. ^aThree patients in each group did not receive study treatment. ^bSubsequent approved treatment was defined as treatment with an agent associated with improved overall survival (abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, sipuleucel-T, or radium-223). ^cTotal sample size is the safety population of each treatment group. ^dOther includes bicalutamide, cabazitaxel, cisplatin, cyclophosphamide, darolutamide, dexamethasone, ethinylestradiol, flutamide, investigational antineoplastic drugs (commercially available ERLEADA, PD-L1-inhibitor plus ERLEADA, pTVG-HP plasmid DNA-vaccine), and rucaparib. Patients could receive more than one subsequent therapy. Continuing ADT was not considered a subsequent therapy.

Safety – Primary Analysis

The safety population included all patients who received at least 1 dose of study drug.
Treatment discontinuation due to progressive disease was reported in 155 (19.3%) patients in the ERLEADA group and in 210 (52.8%) patients in the placebo group.
Treatment discontinuation due to adverse events (AEs) was reported in 85 (10.6%) and 28 (7.0%) patients who received ERLEADA or placebo, respectively.¹ Rash was the most common AE leading to treatment discontinuation (2.4% vs 0), dose reduction (2.7% vs 0.3%), and dose interruption (6.8% vs 1.3%) in the ERLEADA group vs the placebo group, respectively.²⁰
AEs were associated with death in 10 patients in the ERLEADA group: prostate cancer (n=2), sepsis (n=2), acute myocardial infarction (n=1), cardiorespiratory arrest (n=1), cerebral hemorrhage (n=1), myocardial infarction (n=1), multiple organ dysfunction (n=1), and pneumonia (n=1).

Safety – Final OS Analysis

AEs that occurred in ≥15% of patients in the ERLEADA group (all grades) included: fatigue (33%), hypertension (28%), diarrhea (23%), fall (22%), nausea (20%), arthralgia (20%), weight decreased (20%), back pain (18%), and hot flush (15%).²
Treatment discontinuation due to progressive disease was reported in 343 (43%) of patients in the ERLEADA group, 238 (74%) of patients in the placebo group, and 11 (14%) of patients in the crossover group.¹⁹
Treatment discontinuation due to AEs was reported in 122 (15%), 27 (8.4%), and 8 (11%) of patients in the ERLEADA, placebo, and crossover groups respectively.¹⁹
One AE leading to death (myocardial infarction) was considered potentially related to ERLEADA.²

Additional Information

Additional information regarding the SPARTAN study, including the clinical study report, protocol, and statistical analysis plan, can be found at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm (scroll to the “Sponsor Clinical Study Reports ARN-509-003 SPARTAN NCT # 01946204” section at the bottom of the web page).

TITAN Study

TITAN (NCT02489318) was the phase 3, randomized, double-blind, placebo-controlled, multicenter study that evaluated the efficacy and safety of ERLEADA in patients with mCSPC (N=1052).⁴ Patients were randomized 1:1 to receive either ERLEADA orally at a dose of 240 mg once daily (n=525) or placebo once daily (n=527). All patients received a concomitant GnRH analog or had a bilateral orchiectomy.²¹

PFS2, defined 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, was an exploratory endpoint (Figure: TITAN Study Design)⁴^,⁵

TITAN Study Design⁴^,⁵^,²²

Abbreviations: : ADT, androgen deprivation therapy; CT, computerized tomography; ECOG PS, Eastern Cooperative Oncology Group performance status; GnRH, gonadotropin-releasing hormone; mCSPC, metastatic castration-sensitive prostate cancer; MRI, Magnetic resonance imaging; OS, overall survival; PCWG2, prostate cancer clinical trials working group 2; PFS2, second progression-free survival; PO, by mouth; R, randomization; RECIST, Response evaluation criteria in solid tumors; rPFS, radiographic progression-free survival.
^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.

Results

Patient Characteristics

Patient demographic and disease characteristics were well balanced between the 2 groups, and there were no significant differences.

Efficacy

Primary Analysis

Median treatment duration was 20.5 months with ERLEADA and 18.3 months with placebo.
At the clinical cutoff date, 66.2% and 46.1% of patients in the ERLEADA and placebo groups remained on treatment, respectively.
At the final analysis for radiographic progression-free survival (rPFS; following 365 events), treatment with ERLEADA significantly improved rPFS with a 52% risk reduction of radiographic progression or death (median rPFS could not be estimated in the ERLEADA group and 22.1 months in the placebo group; HR, 0.48; 95% CI, 0.39-0.60; P<0.001).
At the primary analysis for OS (following 200 deaths), treatment with ERLEADA significantly improved OS with a 33% risk reduction of death (median OS could not be estimated in either group; HR, 0.67; 95% CI, 0.51-0.89; P=0.005).
Time to cytotoxic chemotherapy was significantly longer in the ERLEADA group compared to placebo group (HR, 0.39; 95% CI, 0.27-0.56; P<0.001).
Based on preplanned hierarchical testing sequence, formal significance testing was not performed for the other secondary endpoints because there was no significant difference between groups for time to pain progression (P=0.12).
Based on results from this first planned interim analysis, the IDMC recommended unblinding to allow crossover of patients receiving placebo to receive ERLEADA.
- After unblinding of the study, 208 (39.5%) patients in the placebo group received therapy with ERLEADA plus ADT (crossover group).⁶

PFS2 and Subsequent Treatments – Primary Analysis

Median PFS2 was longer in the ERLEADA group in comparison to the placebo group (HR, 0.66; 95% CI, 0.50–0.87). The median PFS2 was NR in the ERLEADA group or placebo group. The 24-month event-free rates for PFS2 were 81% and 72% in the ERLEADA and placebo groups, respectively.⁵
- Of the patients that discontinued study treatment, 51.2% of ERLEADA-treated patients and 70.1% of placebo-treated patients received subsequent systemic therapy for prostate cancer (Table: First Subsequent Systemic Prostate Cancer Therapy – Primary Analysis).⁵
- The most common first subsequent treatment was docetaxel (17.1% in the ERLEADA group and 24.7% in the placebo group), and the most common first subsequent hormonal therapy was abiraterone acetate plus prednisone (12.4% in the ERLEADA group and 16.6% in the placebo group).⁵

First Subsequent Systemic Prostate Cancer Therapy – Primary Analysis⁵

	ERLEADA Group (n=525)	Placebo Group (n=527)
Discontinued study treatment, n	170	271
Discontinued due to disease progression, n (%)	99 (18.9)	227 (43.1)
Patients with life-prolonging subsequent therapy for prostate cancer,^a n (%)	64 (37.6)	165 (60.9)
Patients receiving subsequent systemic prostate cancer therapy at data cutoff,^b n (%)	87 (51.2)	190 (70.1)
First subsequent therapy, n (%)
Hormonal therapy	44 (25.9)	98 (36.2)
Abiraterone acetate plus prednisone	21 (12.4)	45 (16.6)
Bicalutamide	16 (9.4)	31 (11.4)
Enzalutamide	3 (1.8)	17 (6.3)
Other^c	4 (2.4)	5 (1.8)
Chemotherapy	35 (20.6)	73 (26.9)
Docetaxel	29 (17.1)	67 (24.7)
Cabazitaxel	1 (0.6)	2 (0.7)
Other^d	5 (2.9)	4 (1.5)
Other Therapy	8 (4.7)	19 (7.0)
Radium-223	2 (1.2)	4 (1.5)
Sipuleucel-T	2 (1.2)	5 (1.8)
Other^e	4 (2.4)	10 (3.7)
^aIncluded docetaxel, abiraterone acetate plus prednisone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T. ^bSome patients were unblinded after discontinuation and prior to first subsequent therapy to allow enrollment in a subsequent clinical trial. ^cIncluded diethylstilbestrol, flutamide, and cyproterone. ^dIncluded etoposide, paclitaxel, estramustine, carboplatin, and cisplatin. ^eIncluded zoledronic acid, clodronate, prednisolone, and prednisone.

Final OS Analysis

The median treatment duration was 39.3 months in the ERLEADA group, 20.2 months in the placebo group, and 15.4 months in the crossover group.⁶
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.⁶
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% reduction in the risk of death. The final OS analysis provided mature OS results without formal statistical inference.⁶
The median time to cytotoxic chemotherapy was NR in either group (HR, 0.47; 95% CI, 0.35-0.63; nominal P<0.0001). This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.⁶

PFS2 and Subsequent Treatments – Updated Analysis

PFS2 events occurred in 173 (33.0%) patients in the ERLEADA group and in 246 (46.7%) patients in the placebo group.²³
The median PFS2 was NR in the ERLEADA group and was 44 months in the placebo group (HR, 0.62; 95% CI, 0.51-0.75; nominal P<0.0001). This endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established.
- Of the patients who were alive at treatment discontinuation, 48.6% of ERLEADA-treated patients and 64.1% of placebo-treated patients received first subsequent systemic therapy for prostate cancer (Table: First Subsequent Systemic Prostate Cancer Therapy – Updated Analysis).⁶^,²³
- Among patients who were alive at treatment discontinuation, the most common first subsequent chemotherapy was docetaxel (17.0% in the ERLEADA group and 22.6% in the placebo group), and the most common first subsequent hormonal therapy was abiraterone acetate plus prednisone (10.9% in the ERLEADA group and 18.8% in the placebo group).²³
- Of 138 patients in the ERLEADA group and 261 patients in the placebo group who discontinued treatment due to progressive disease and remained alive, 54.3% and 57.9%, respectively, received first subsequent life-prolonging therapy for prostate cancer, with docetaxel and abiraterone acetate plus prednisone being the most common.⁶

First Subsequent Systemic Prostate Cancer Therapy – Updated Analysis⁶^,²³

	ERLEADA Group (n=525)	Placebo Group (n=527)
Discontinued study treatment and remained alive,^a n (%)	247 (47.0)^b	345 (65.5)
Patients with first subsequent systemic therapy for prostate cancer, n (%)	120 (48.6)	221 (64.1)
Patients with first life-prolonging subsequent therapy for prostate cancer,^c n (%)	89 (36.0)	173 (50.1)
First subsequent systemic therapy, n (%)
Hormonal therapy^d	58 (23.5)	124 (35.9)
Abiraterone acetate plus prednisone	27 (10.9)	65 (18.8)
Bicalutamide	16 (6.5)	30 (8.7)
Enzalutamide	9 (3.6)	24 (7.0)
Flutamide	2 (0.8)	4 (1.2)
Diethylstilbestrol	2 (0.8)	0
Cyproterone	0	2 (0.6)
Chemotherapy^d	50 (20.2)	88 (25.5)
Docetaxel	42 (17.0)	78 (22.6)
Carboplatin	4 (1.6)	4 (1.2)
Cabazitaxel	2 (0.8)	5 (1.4)
Etoposide	2 (0.8)	3 (0.9)
Paclitaxel	2 (0.8)	1 (0.3)
Cisplatin	0	2 (0.6)
Other therapy^d	32 (13.0)	63 (18.3)
Prednisone	7 (2.8)	20 (5.8)
Prednisolone	6 (2.4)	12 (3.5)
Zoledronic	6 (2.4)	14 (4.1)
Radium-223	5 (2.0)	5 (1.4)
Sipuleucel-T	4 (1.6)	5 (1.4)
Dexamethasone	4 (1.6)	4 (1.2)
Abbreviation: ADT, androgen deprivation therapy. ^aDenominator for all percentages in this table.^bIncluded 1 patient who did not receive ERLEADA.^cContinuing ADT was not considered a subsequent therapy. ^dSubsequent therapies included in this table are those that ≥2 patients received in either treatment group.

Safety

Primary Analysis

The safety population included all patients who received at least one dose of study drug; one patient in the ERLEADA group discontinued the study prior to receiving a dose.
Treatment discontinuation due to progressive disease was reported in 99 (18.9%) patients in the ERLEADA group and in 227 (43.1%) patients in the placebo group.
Treatment discontinuation due to AEs was reported in 42 (8.0%) and 28 (5.3%) patients who received ERLEADA or placebo, respectively. Rash 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.⁵
Ischemic heart disease was reported in 4.4% and 1.5% of patients in the ERLEADA and placebo groups, respectively; two patient deaths due to ischemic events were reported in each group.
AEs associated with death in 10 patients in the ERLEADA group were: acute kidney injury (n=2), acute myocardial infarction, myocardial infarction, cardiogenic shock, sudden cardiac death, cardio-respiratory arrest, respiratory failure, cerebrovascular accident, and large intestinal ulcer perforation (all n=1). AEs associated with death in 16 patients in the placebo group were: sudden death (n=2), respiratory failure (n=2), acute myocardial infarction, acute coronary syndrome, cardiac failure, intracranial hemorrhage, subdural hemorrhage, vascular rupture, pulmonary embolism, sepsis, urosepsis, hypothermia, suicide, and unspecified death (all n=1).⁵

Final OS Analysis

Treatment-emergent AEs of all grades that occurred in ≥10% of patients in the ERLEADA group included: hot flush (23.1%), back pain (20.6%), fatigue (20.4%), rash (20.2%), arthralgia (19.7%), hypertension (19.5%), pain in extremity (13.4%), anemia (13.2%), constipation (11.3%), pruritus (11.1%), diarrhea (10.7%), and weight increased (10.5%).²³
In the ERLEADA group, grade 3 to 4 TEAEs occurred in 49.4% of patients.²³
The most common treatment-related TEAEs in the ERLEADA group were rash (17.6%) and fatigue (13.5%).⁶^,²³
Treatment discontinuation due to progressive disease was reported in 138 (26.3%) patients in the ERLEADA group, 245 (76.8%) patients in the placebo group, and 16 (7.7%) patients in the crossover group.⁶
Treatment discontinuation due to TEAEs was reported in 62 (11.8%) patients in the ERLEADA group, 30 (5.7%) patients in the placebo group, and 16 (7.7%) patients in the crossover group.²³
TEAEs led to death in 20 (3.8%) patients in the ERLEADA group, 17 (3.2%) patients in the placebo group, and 7 (3.4%) patients in the crossover group. There were no treatment-related deaths.⁶^,²³

Additional Analyses

A post hoc analysis evaluated PFS2 by first subsequent therapy following discontinuation of study treatment, specifically hormonal compared to taxane therapy, in patients enrolled in the TITAN study.⁷
- Of the 87 patients in the ERLEADA group that received subsequent systemic therapy, 24 (27.6%), 30 (34.5%), and 33 (37.9%) patients received hormonal, taxane, or other systemic therapy, respectively. Of the 190 patients in the placebo group who received subsequent systemic therapy, 62 (32.6%), 69 (36.3%), and 59 (31.1%) patients received hormonal, taxane, or other systemic therapy, respectively.
- The ERLEADA group demonstrated a reduced risk of PFS2 compared to 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 therapy (median, NR in either group; HR, 0.634; 95% CI, 0.456-0.881; P=0.0062) as the first subsequent therapy.
A post hoc analysis evaluated the efficacy and safety outcomes for patients with high- and low-risk disease enrolled in the TITAN study.⁸
- High-risk disease was defined as ≥2 of the following risk factors: Gleason score ≥8, ≥3 bone lesions, the presence of measurable visceral metastasis.
- A summary of first subsequent therapies following discontinuation of TITAN study treatment is described in Table: First Subsequent Systemic Prostate Cancer Therapy - Post Hoc Analysis by High- and Low-Risk Disease.
- Patients in the ERLEADA group considered high-risk at baseline had significantly longer PFS2 compared with the placebo group (HR, 0.617; 95% CI, 0.441-0.863; P=0.005). PFS2 among patients with low-risk disease did not significantly differ between the ERLEADA and the placebo groups (HR, 0.693; 95% CI 0.428-1.124; P=0.1351).

First Subsequent Systemic Prostate Cancer Therapy - Post Hoc Analysis by High- and Low-Risk Disease⁸

Therapy, n (%)	High-Risk Disease		Low-Risk Disease
Therapy, n (%)	ERLEADA Group n=107^a	Placebo Group n=175^a	ERLEADA Group n=63^a	Placebo Group n=96^a
Patients with subsequent therapy^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 adverse events.

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).⁹
- A summary of PFS2 in different subgroups is described in Table: PFS2 by Clinical Subgroup.
- A summary of first subsequent therapies following discontinuation of TITAN study treatment is described in Table: Select First Subsequent Systemic Prostate Cancer Therapy - Post Hoc Analysis by Clinical Subgroup.

PFS2 by Clinical Subgroup⁹

	Synchronous/ High-Volume		Synchronous/ Low-Volume		Metachronous/ High-Volume		Metachronous/ Low-Volume
	ERLEADA Group n=273	PBO Group n=294	ERLEADA Group n=138	PBO Group n=147	ERLEADA Group n=32	PBO Group n=28	ERLEADA Group n=53	PBO Group n=31
Median PFS2, months	NR	33.1	NR	NR	NR	38.6	NR	NR
HR (95% CI)	0.64 (0.51-0.82)		0.61 (0.38-0.97)		0.63 (0.30-1.33)		0.22 (0.09-0.56)
Nominal P-Value^a	<0.001		0.04		0.23		0.002
^aThis endpoint was not adjusted for multiple comparisons. Therefore, the P-value displayed is nominal, and statistical significance has not been established. Abbreviations: CI, confidence interval; HR, hazard ratio; NR, not reached; PBO, placebo; PFS2, second progression-free survival.

Select First Subsequent Systemic Prostate Cancer Therapy - Post Hoc Analysis by Clinical Subgroup⁹

Therapy, n (%)	Synchronous/ High-Volume^a		Synchronous/ Low-Volume^b		Metachronous/ High-Volume^c		Metachronous/ Low-Volume^d
Therapy, n (%)	ERLEADA Group n=153^e	PBO Group n=212^e	ERLEADA Group n=39^e	PBO Group n=80^e	ERLEADA Group n=18^e	PBO Group n=21^e	ERLEADA Group n=23^e	PBO Group n=20^e
AAP	26 (17)	60 (28)	7 (18)	22 (28)	4 (22)	6 (29)	2 (8.7)	5 (25)
Enzalutamide	11 (7.2)	28 (13)	3 (7.7)	18 (23)	2 (11)	5 (24)	2 (8.7)	4 (20)
Docetaxel	43 (28)	70 (33)	5 (13)	26 (33)	3 (17)	6 (29)	3 (13)	4 (20)
Cabazitaxel	11 (7.2)	22 (10)	2 (5.1)	7 (8.8)	1 (5.6)	0	1 (4.3)	0
Radium-223	8 (5.2)	13 (6.1)	2 (5.1)	0	1 (5.6)	2 (9.5)	1 (4.3)	1 (5.0)
Sipuleucel-T	1 (0.7)	3 (1.4)	2 (5.1)	1 (1.3)	0	2 (9.5)	1 (4.3)	1 (5.0)
^aSynchronous/high-volume ERLEADA group, n=273; PBO group, n=294. ^bSynchronous/low-volume ERLEADA group, n=138; PBO group, n=147. ^cMetachronous/high-volume ERLEADA group, n=32; PBO group, n=28. ^dMetachronous/low-volume ERLEADA group, n=53; PBO group, n=31.^eNumber of patients alive at treatment discontinuation. Abbreviations: AAP, abiraterone acetate plus prednisone; PBO, placebo.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 25 March 2024. Summarized in this response are relevant data limited to the phase 3 SPARTAN study in patients with nmCRPC and phase 3 TITAN study in patients with mCSPC.

References

Show

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22	Chi KN, Chowdhury S, Bjartell A, et al. Final analysis results from TITAN: a phase 3 study of apalutamide vs placebo in patients with metastatic castration-sensitive prostate cancer receiving androgen deprivation therapy. Rapid abstract presentation presented at: American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium; February 11-13, 2021; Virtual.
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