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The regimen of apalutamide, abiraterone acetate, and prednisone showed viability as an ADT-free alternative in patients with advanced prostate cancer with noncastrate testosterone levels.
The androgen deprivation therapy (ADT)-free regimen of apalutamide (APA; Erleada) combined with abiraterone acetate (Zytiga) and prednisone (AAP) showed strong activity in advanced castration-sensitive prostate cancer (CSPC), according to findings from the phase 2 LACOG 0415 study shared during the 2020 American Society of Clinical Oncology Virtual Scientific Program.
In the study, 79.5% of patients with advanced CSPC treated with APA plus AAP reached a PSA level of ≤0.2 ng/mL at week 25. The rate was comparable to the 75.6% rate achieved in the study by a regimen of ADT plus AAP, showing the ADT-free regimen to be a potentially viable alternative in this setting.
“This is the first randomized trial that evaluated the efficacy and safety of androgen signaling inhibitors without castration in patients with advanced CSPC,” said lead study author Fernando C. Maluf, MD, Latin American Cooperative Oncology Group. “Apalutamide plus abiraterone demonstrated high efficacy in terms of PSA decline.”
The ongoing, open-label, noncomparative LACOG 0415 trial (NCT02867020) included 128 asymptomatic to moderately symptomatic patients with advanced CSPC and an indication to start ADT. At baseline, 17.2% of patients had biochemical recurrence (PSA ≥4 ng/mL and PSA doubling time <10 months, or PSA ≥20 ng/mL); 8.6% had node-positive disease and were not candidates for local therapy; and 74.2% of patients had metastatic disease. The median patient age was 70 years (range, 49-88).
The median PSA was 22.5 ng/mL (IQR, 6.9-117.4), and the median testosterone level was 409.2 ng/mL (IQR, 319.3-500.5). Gleason score at diagnosis was ≤6 (7.8%), 7 (35.2%), or ≥8 (57%). All patients except 1 had an ECOG performance status of 0 or 1. Overall, 46.2% of patients had de novo metastatic status at diagnosis. Prior treatments included radiotherapy (36.7%), prostatectomy (43%), and neo(adjuvant) ADT (10.9%). Prior ADT could not have occurred within 12 months of study enrollment.
Patients were randomized in a 1:1:1 ratio to ADT plus AAP (n = 42), APA alone (n = 42), or APA plus AAP (n = 44). Abiraterone was administered at 1000 mg orally daily and apalutamide was administered orally at 240 mg daily.
The primary end point was the rate of patients achieving a PSA level <0.2 ng/mL at week 25. This was measured in the modified intention-to-treat (mITT) population and in a sensitivity analysis. The mITT population included only patients with an evaluable PSA at week 25; this included 41 patients in the ADT plus AAP arm, 40 patients in the APA alone arm, and 39 patients in the APA plus AAP arm. The sensitivity analysis included all randomized patients, categorizing missing PSA data at week 25 as failures.
In the mITT analysis for the primary end point, 79.5% (95% CI, 63.5-90.7) of patients in the APA plus AAP arm and 60% (95% CI, 43.3-75.1) of the patients in the APA arm had a PSA ≤0.2 ng/ml at week 25. The rate was 75.6% (95% CI, 59.7-87.6) in the ADT plus AAP arm. The APA arm did not meet the study’s primary end point, as the trial design established the threshold for success as 65% of patients in a cohort having a PSA ≤0.2 ng/ml at week 25.
In the sensitivity analysis, 70.5% (95% CI, 54.8-83.2) in the APA plus AAP arm and 57.1% (95% CI, 41-72.3) of patients in the APA arm had a PSA ≤0.2 ng/ml at week 25. The rate per the sensitivity analysis was 73.8% (95% CI, 58-86.1) in the ADT plus AAP arm.
Several secondary outcomes were only measured in the mITT population. The rate of patients with a PSA decline ≥50% at week 25 was 100% in the ADT plus AAP arm, 92.5% in the APA alone arm, and 100% in the APA plus AAP arm. The rates of patients with a PSA decline ≥80% at week 25 were 100%, 90%, and 97.4%, respectively, and the rates of patients with PSA progression at week 25 were 0, 7.5% and 0, respectively.
“Testosterone levels from baseline up to week 25 varied significantly among the 3 arms. In patients treated with apalutamide alone, there was a 134.3% increase in testosterone level, while in patients treated with apalutamide plus abiraterone there was a 73.8% decrease up to week 25. And, as expected, in patients who received ADT plus abiraterone, the [testosterone level] decreased by 97.4%,” said Maluf.
The safety analysis included all 128 patients. In the ADT plus AAP arm, all-grade treatment-related adverse events (TRAEs) occurred in 71.4% of patients, with grade 3/4 TRAEs occurring in 19%. One patient discontinued treatment and it was due to toxicity.
In the APA monotherapy arm, all-grade TRAEs occurred in 81% of patients, with 16.7% being grade 3/4. One patient discontinued treatment due to toxicity, and 1 patient discontinued due to glioma. In the APA plus AAP cohort, TRAEs of any grade occurred in 81.8% of patients, with grade 3/4 TRAEs occurring in 22.7%. Four patients in this cohort discontinued treatment due to toxicity and 2 patients withdrew from trial.
Maluf highlighted a few specific AEs. All-grade gynecomastia occurred in 55% of the APA arm, compared with 20% of the APA plus AAP arm, and 7% of the ADT plus AAP arm. Breast pain across all grades occurred in 14%, 5%, and 0% of the 3 arms, respectively.
Hot flushes, hypertension, and hyperglycemia, Maluf noted, were more common in the 2 abiraterone combination arms compared with the APA alone arm. Rash and pruritus were more prevalent in the APA arms, either alone or combined with AAP.
“Quality of life (FACT-P) from baseline up to week 25 remained consistent among the 3 arms,” said Maluf.
Regarding next steps for this research, Maluf said, “The substitution of castration by androgen signaling inhibitors is still an open field and further research is necessary not only to answer this question but also to determine which subgroup of patients may benefit from this new strategy.”
Maluf FC, Fay AP, Vinícius Carrera Souza VC, et al. Phase II randomized study of abiraterone acetate plus prednisone (AAP) added to ADT versus apalutamide alone (APA) versus AAP+APA in patients with advanced prostate cancer with noncastrate testosterone levels: (LACOG 0415). J Clin Oncol 38: 2020 (suppl; abstr 5505). doi: 10.1200/JCO.2020.38.15_suppl.5505