Adding apalutamide to ADT effective in high-risk biochemically relapsed prostate cancer

Prostate Cancer

Prostate Cancer

Intensification of androgen-deprivation therapy (ADT) with the addition of the androgen receptor inhibitor apalutamide (Erleada) showed potential as a treatment for patients with high-risk biochemically relapsed prostate cancer, according to findings from the phase 3 PRESTO trial presented at the 2022 ESMO Congress.1

The findings also showed, however, that the further addition of abiraterone acetate (Zytiga) and prednisone to the apalutamide/ADT regimen did not significantly boost clinical outcomes.

At a median follow-up of 21.5 months, the median PSA progression-free survival (PSA PFS) was 24.9 months (95% CI, 23.3-32.3) with apalutamide plus ADT versus 20.3 months (95% CI, 18.2-22.9) with ADT alone (HR, 0.52; 95% CI, 0.35-0.77; P = .00047).

At a median follow-up of 21.3 months, the median PSA PFS was 26.0 months (95% CI, 22.9-32.5) with ADT + apalutamide + abiraterone/prednisone versus 20.0 months (95% CI, 18.2-22.5) with ADT alone (HR, 0.48; 95% CI, 0.32-0.71; P = .00008).

“The addition of apalutamide to ADT for a finite duration of treatment leads to a statistically significant prolongation of PSA PFS without an adverse impact on time to testosterone recovery,” said lead author Rahul Aggarwal, MD, associate professor of Hematology/Oncology, University of California, San Francisco (UCSF), and associate director for Clinical Sciences, UCSF Helen Diller Family Comprehensive Cancer Center.

“Though not powered to compare experimental arms, there does not appear to be a substantial additional clinical benefit with the addition of abiraterone and prednisone to apalutamide, and there was increased toxicity in this arm,” added Aggarwal.

Inclusion criteria for the open-label PRESTO study (NCT03009981) were prior radical prostatectomy with subsequent biochemical recurrence (PSA >.05 ng/mL) and a PSA doubling time (PSA-DT) ≤9 months. Patients could not have metastases found on conventional imaging, including a CT and bone scan, and must have received prior adjuvant/salvage radiation unless not eligible for radiotherapy. Prior ADT was allowed, as long as the last dose was >9 months prior to study enrollment.

There were 503 patients randomized in a 1:1:1 ratio to receive ADT monotherapy (LHRH analog; Arm A; 166 patients); ADT (LHRH analog) plus apalutamide (Arm B; 168 patients); or ADT + apalutamide + abiraterone + prednisone (Arm C; 169 patients).

“In all 3 arms, patients were treated for a finite duration of 52 weeks in the absence of PSA progression or unacceptable toxicity,” said Aggarwal. “Following treatment completion, patients were followed with mostly lab assessment until PSA progression, at which point, treatment was per investigator discretion.”

The primary end point of the study was to compare each experimental arm (B and C) to the control arm of ADT alone (Arm A) with respect to PSA PFS. “PSA progression was defined as an increase in PSA of nadir + 2 ng/mL during treatment or >0.2 ng/mL following treatment confirmed by repeat measurement,” explained Aggarwal.

Key secondary outcome measures were PSA PFS in the testosterone-evaluable population (subgroup that achieved a serum testosterone level >50 ng/dL following treatment completion), medium time to testosterone recovery (a level >50 ng/dL), and safety.

Aggarwal said patient and disease characteristics at baseline were well balanced among the 3 study arms. Across the overall study population, the median age was 66.7 years (range, 61.2-70.9). The majority of patients on the trial were either White (83.7%), Black or African-American (6.4%), or Asian (2.6%). Regarding ethnicity, 91.1% of patients were non-Hispanic, 5.4% were Hispanic, and 3.6% were “unknown/not reported/missing.”

“It is worth noting that although the investigational sites were broadly geographically distributed across the United States, the enrollment of Black and Hispanic men fell short of US population percentages,” said Aggarwal.

The median PSA at baseline was 1.77 ng/mL. The PSA DT was <3 months for 25.8% of patients and between 3 and 9 months for 74.2% of patients. The median time between radical prostatectomy and baseline was 4.4 years. Overall, 84.7% of patients had prior radiation and 42.35% of patients had prior ADT.

A preplanned subgroup analysis based on stratification by PSA DT showed a consistent benefit with both experimental arms versus the control arm, regardless of the length of PSA DT. In the comparison of apalutamide plus ADT vs ADT alone, the HR for PSA PFS was 0.57 in patients with a PSA DT <3 months and 0.50 in patients with a PSA DT of between 3 and 9 months. Comparing ADT + apalutamide + abiraterone/prednisone vs ADT alone, the HR for PSA PFS was 0.46 and 0.48 in the <3 months and 3-to-9 months PSA DT subgroups, respectively.

Similarly, when assessing PSA PFS in patients with testosterone recovery (testosterone evaluable population), the HR for PSA PFS showed a benefit in both the ADT plus apalutamide arm (HR, 0.53; P = .00197) and the ADT + apalutamide + abiraterone/prednisone arm (HR, 0.60; P = .00851) versus the ADT alone arm that was comparable to the benefit observed in the overall study population.

Aggarwal also noted that, “The addition of apalutamide to ADT did not adversely impact the time to testosterone recovery following treatment completion. With the further addition of abiraterone, we saw a slight prolongation in time to testosterone recovery, though this did not reach statistical significance.”

Regarding safety, Aggarwal explained that the incidence of grade 3/4 and serious adverse events (AEs) was increased with the addition of abiraterone in Arm C. Across the study arms, grade 3/4 AEs occurred in 18.8%, 25.2%, and 37.9% of Arms A, B, and C, respectively, and serious AEs occurred in 8.1%, 8.6%, and 17.4% of the 3 arms, respectively.

While adding apalutamide to ADT did not appear to lead to an increase in the most commonly observed grade ≥2 AEs, the addition of abiraterone in Arm C increased the incidence of grade ≥2 hypertension (30.4%) versus Arm B (22.7%) and Arm A (19.4%).

“Follow-up is ongoing to estimate the impact of ADT plus AR pathway inhibition on patient-reported outcomes, time to castration resistance, and metastasis-free survival,” Aggarwal said in his concluding remarks.

“Given that treatment decisions in biochemically recurrent prostate cancer are often predicated on PSA kinetics alone, ADT plus apalutamide for a fine treatment period could be considered for select high-risk patients with a short PSA doubling time,” he added.


1. Aggarwal R, Heller G, Hillman D, et al. PRESTO: A phase III, open-label study of androgen annihilation in patients (pts) with high-risk biochemically relapsed prostate cancer (AFT-19).Ann Oncol. 2022;33(suppl 7):S808-S869. doi: 10.1016/annonc/annonc1089

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