Apalutamide Boosts 24-Month OS in Real-World Population With Metastatic Castration-Sensitive Prostate Cancer

Image Credit:©Sebastian Kaulitzki – stock.adobe.com

Treatment with apalutamide (Erleada) demonstrated consistent 24-month overall survival (OS) data between real-world patients with metastatic castration-sensitive prostate cancer (mCSPC) and those treated in the phase 3 TITAN trial (NCT02489318).1

These findings, presented at the 50th Annual Oncology Nursing Society Congress, demonstrated that at 24 months after treatment initiation, patients with mCSPC who were not previously treated with androgen receptor pathway inhibitors (ARPIs) and received apalutamide showed a 23% reduction in the risk of death compared with patients treated with enzalutamide (Xtandi; HR, 0.77; 95% CI, 0.62-0.96; P = .019); this OS result was also consistent when using all available follow-up (HR, 0.77; 95% CI, 0.64-0.93; nominal P = .008). Patients treated with apalutamide after 24 months post-index had a 26% reduction in the risk of death vs patients treated with abiraterone acetate (Zytiga; HR, 0.74; 95% CI, 0.59-0.93; P = .010); this OS result was also consistent when using all available follow-up (HR, 0.72; 95% CI, 0.59-0.88; nominal P < .001).

“All 3 agents have demonstrated statistically significant reductions in disease progression and death as compared with androgen deprivation therapy [ADT] alone in patients with mCSPC in phase 3 trials,” said Kelly Hastings, ANP-BC, MSN, senior medical science liaison at Johnson & Johnson Innovative Medicine, in a poster presentation of the findings. “However, there are currently no head-to-head studies comparing the survival outcomes [or disease progression] between apalutamide and either of the 2 agents in ARPI-naive patients with mCSPC.”

In September 2019, the FDA approved apalutamide for the treatment of patients with mCSPC, which was based on data from the phase 3 TITAN trial.2 Results from the final analysis revealed that apalutamide plus ADT led to a 35% reduction in the risk of death compared with placebo plus ADT, with a median OS that was not reached (NR) vs 52.2 months, respectively (HR, 0.65; 95% CI, 0.53-0.79; P < .0001).3 In December 2019, the FDA approved enzalutamide for the treatment of patients with mCSPC, which was based on findings from the phase 3 ARCHES trial (NCT02677896).4 Of note, enzalutamide plus ADT significantly reduced the risk of radiographic progression or death vs placebo plus ADT (HR, 0.39; 95% CI, 0.30-0.50; P < .001).5 Moreover, the FDA approved abiraterone acetate with prednisone for high-risk mCSPC in February 2018 based on findings from the phase 3 LATITUDE trial (NCT0175285).6 In the final OS analysis of the study, the median OS was significantly longer in the abiraterone acetate cohort at 53.3 months (95% CI, 48.2-NR) vs 36.5 months in the placebo cohort (95% CI, 33.5-40.0; HR, 0.66; 95% CI, 0.56-0.78; P < .0001).7

Delving Into the Real-World Study Design

The rationale of the real-world study was to compare the 24-month OS outcomes in the proportion of ARPI-naive patients with mCSPC who recently initiated apalutamide vs enzalutamide or apalutamide vs abiraterone acetate.1

In the study, patients were evaluated as having mCSPC if they had a diagnosis code or clinical indicator for bone, nodal, or visceral metastasis, without castration resistance before or on the index date. Patients were also naive to ARPIs and were not previously treated with estrogens, immunotherapy, PARP inhibitors, or radiopharmaceutical therapy. Notably, castration resistance was evaluated based on a previously published algorithm that incorporated the presence of ADT—identified in both Precision Point Specialty (PPS) Analytics and the Komodo Research Claims Database (KRD)—and prostate-specific antigen (PSA) levels with clinical notes from the electronic medical record by PPS.

Additionally, concurrent use of ADT was not required for study eligibility in the apalutamide, enzalutamide, or abiraterone acetate cohorts. In the abiraterone acetate cohort, concurrent use of prednisone was not required. With a study period between December 16, 2018, and December 31, 2023, patients in the apalutamide cohort (n = 1810) were compared with those in the enzalutamide cohort (n = 1909). Conversely, during a study period of September 17, 2018, to December 31, 2023, patients in the apalutamide cohort (n = 1879) were compared with those in the abiraterone acetate cohort (n = 2073).

A power calculation was used to verify that the sample size was adequate to detect statistically significant differences in OS between each of the cohorts. Retrospective longitudinal causal analyses including ARPI-naive patients with mCSPC were conducted, which utilized propensity score-weighted cohorts initiated on apalutamide or enzalutamide, and on apalutamide or abiraterone acetate. The index date was defined as the first dispensation or paid pharmacy claim for apalutamide or enzalutamide on or after the FDA approval date for enzalutamide in the apalutamide vs enzalutamide analysis; and for apalutamide or abiraterone acetate on or after the regulatory decision for apalutamide in the apalutamide vs abiraterone acetate analysis. Baseline characteristics were evaluated in the 12 months before the index date; treatment patterns were observed from the index date for a period spanning up to 24 months.

Differences in baseline characteristics between the apalutamide and enzalutamide cohorts, and the apalutamide and abiraterone acetate cohorts, were accounted for by inverse probability of treatment weighting (IPTW) based on propensity score. Of note, the propensity score was obtained from a logistic regression model in which the index treatment was the dependent variable with baseline characteristics as independent variables. These baseline characteristics included age, race, geographic region, payer type, index year, time between metastasis and index date, time between prostate cancer diagnosis and index date, metastasis type, Quan-Charlson Comorbidity Index, de novo prostate cancer diagnosis, ADT use overlapping index date, prior first-generation antiandrogens, prior chemotherapy, baseline PSA levels, and initial Gleason score. The proportion of patients surviving by 24 months post-index was assessed using a weighted Kaplan-Meier analysis; weighted Cox proportional hazards models were used to assess the causal relationship between index treatment and OS.

Baseline Patient Characteristics

In patients from the apalutamide vs enzalutamide cohorts, the mean age was 73.0 years in both respective cohorts. Races included White (apalutamide, 59.8%; enzalutamide, 59.4%), Black (22.5%; 22.7%), Hispanic/Latino (7.5%; 7.6%), other (4.4%; 4.6%), and unknown (5.8%; 5.7%). Metastasis types included bone (71.9%; 72.8%), nodal (49.0%; 48.1%), visceral (19.7%; 20.8%), and multiple sites (26.8%; 26.1%). De novo prostate cancer was reported in 56.2% of patients in both cohorts; concurrent use of ADT was reported in 79.2% and 77.8% of patients in the respective cohorts. PSA levels included less than 0.2 ng/mL (15.5%; 14.8%), greater than 0.2 ng/mL to less than 2 ng/mL (16.1%; 15.8%), greater than 2 ng/mL to less than 5 ng/mL (9.9%; 9.5%), greater than 5 ng/mL to less than 10 ng/mL (9.1%; 8.6%), greater than 10 ng/mL (29.9%; 29.5%), and unknown (19.5%; 21.7%).

The mean ages in the apalutamide vs abiraterone acetate cohorts were 72.1 years and 71.9 years, respectively. Races included White (apalutamide, 61.7%; abiraterone acetate, 62.5%), Black (19.1%; 18.0%), Hispanic/Latino (7.5%; 7.3%), other (4.5%; 4.8%), and unknown (7.1%; 7.3%). Metastatic types included bone (66.5%, 66.2%), nodal (52.9% each), visceral (21.1%; 23.0%), and multiple sites (25.4%; 23.7%). De novo prostate cancer was observed in 58.5% and 59.0% of patients in the respective cohorts; concurrent use of ADT was reported in 76.8% and 74.0% of patients. PSA levels included less than 0.2 ng/mL (15.3%; 14.4%), greater than 0.2 ng/mL to less than 2 ng/mL (15.2%; 14.3%), greater than 2 ng/mL to less than 5 ng/mL (9.9%; 9.3%), greater than 5 ng/mL to less than 10 ng/mL (9.0%: 8.3%), greater than 10 ng/mL (28.4%; 27.8%), and unknown (22.2%; 25.9%).

“Baseline patient characteristics were generally well-balanced between the weighted cohorts in the 2 analyses, with standardized differences of less than 10%,” the poster authors wrote.

Real-World Treatment Patterns and Study Limitations

In the apalutamide vs enzalutamide analysis, the median follow-up period was 20.1 months (mean, 17.2) in those who initiated apalutamide and enzalutamide, respectively. Of note, the median duration of continuous ARPI use, with a 90-day gap between treatments to define discontinuation, was 6.9 months (mean, 9.6) in the apalutamide cohort and 6.4 months (mean, 8.6) in the enzalutamide cohort.

Based on the apalutamide vs abiraterone acetate analysis, the median follow-up period was 19.5 months (mean, 16.8) in patients who initiated apalutamide and 19.0 months (mean, 16.3) in those who initiated abiraterone acetate. Specifically, the median duration of continuous ARPI use, including the 90-day gap in treatments to define discontinuation, was 6.6 months (mean, 9.3) vs 8.9 months (mean, 10.7) in those who initiated apalutamide or abiraterone acetate, respectively.

Limitations of this real-world study included the potential for selection and information bias because of miscoding or misclassification in clinical records or claims data, a sole database reflection of a community urology perspective, missing deaths from KRD despite high capture rates of 90% or greater, residual differences post-IPTW associated with a high-risk indication for abiraterone acetate, and the confinement that the regression analysis could only adjust for measured covariates with the potential of remaining confounding variables.

“In phase 3 trials, OS was assessed at prespecified time points. In these real-world studies, OS was assessed [for] 24 months for evaluation of statistical comparison. Longer follow-up may better estimate the full clinical benefit of apalutamide,” the poster authors concluded.

References

1. Shore N, Lowentritt B, Khilfeh I, Du S, Ellis L, Bilen MA. Real-world head-to-head studies evaluating overall survival with apalutamide and abiraterone acetate or enzalutamide in patients with metastatic castration-sensitive prostate cancer. Presented at: 50th Annual Oncology Nursing Society Congress; April 9-13, 2025; Denver, Colorado. Abstract I32.
2. FDA approves apalutamide for metastatic castration-sensitive prostate cancer. FDA. Updated September 18, 2019. Accessed April 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-metastatic-castration-sensitive-prostate-cancer
3. 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. doi:10.1200/JCO.20.03488
4. FDA approves enzalutamide for metastatic castration-sensitive prostate cancer. FDA. Updated December 17, 2019. Accessed April 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enzalutamide-metastatic-castration-sensitive-prostate-cancer
5. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799
6. FDA approves abiraterone acetate in combination with prednisone for high-risk metastatic castration-sensitive prostate cancer. FDA. Updated February 8, 2018. Accessed April 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-abiraterone-acetate-combination-prednisone-high-risk-metastatic-castration-sensitive
7. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomized, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8