Apalutamide Makes Its Case in Biochemically Recurrent Nonmetastatic Prostate Cancer

A 1-year period of intensified androgen receptor blockade prolonged prostate-specific antigen progression-free survival (PSA-PFS) compared with androgen deprivation therapy (ADT) alone for patients with high-risk, biochemically recurrent prostate cancer, according to interim results from a phase III trial.

In the three-arm PRESTO study, adding either apalutamide (Erleada) or apalutamide plus abiraterone acetate (Zytiga) and prednisone to an ADT backbone prolonged median PSA-PFS by about 4 to 6 months:

• Apalutamide: 24.9 vs 20.3 months with ADT alone (HR 0.52, 95% CI 0.35-0.77, P=0.00047)
• Apalutamide plus abiraterone and prednisone: 26 vs 20 months (HR 0.48, 95% CI 0.32-0.71, P=0.00008)

“Although the study was not powered to directly compare between the two experimental arms, there did not appear to be a substantial clinical benefit with the further addition” of abiraterone and prednisone, wrote Rahul Aggarwal, MD, of the University of California San Francisco, and colleagues in the Journal of Clinical Oncology, concluding that apalutamide plus ADT “should be considered” in patients with high-risk, biochemically recurrent prostate cancer.

However, in an editorial accompanying the study, Daniel Childs, MD, of the Mayo Clinic in Rochester, Minnesota, and colleagues, called the use of PSA-PFS as a primary endpoint “problematic,” and pointed out that a rising PSA is not well established as a surrogate for overall survival, the “gold standard” endpoint.

“It is notable yet unsurprising that intensified ADT delayed median PSA progression by the order of 4-6 months. Whether this is enough evidence of benefit to change practice is debatable,” they wrote, adding that it’s unclear whether such a delay in progression would equate to more time off treatment and a delay of metastasis in a group of patients who are largely asymptomatic.

Furthermore, noted Childs and co-editorialists, androgen receptor pathway inhibitors such as apalutamide are very expensive drugs that in some men can cause significant side effects.

“While awaiting secondary endpoints from PRESTO” — which include metastasis-free survival — “we are left to ask ourselves whether delaying PSA rise by a median of 4 months is worth a year of added financial toxicity, time toxicity, and the potential for adverse events,” they wrote.

Aggarwal and his study co-authors argued that intensifying ADT in the biochemically recurrent castration-sensitive setting is further supported by the phase III EMBARK study, in which both ADT plus enzalutamide (Xtandi) and enzalutamide alone prolonged metastasis-free survival and PSA-PFS compared with ADT alone.

To that the editorialists agreed. “On the basis of the data from PRESTO and EMBARK, we believe that fixed-course intensified ADT does have a role in the treatment of selected patients,” they wrote, “but additional biomarkers are needed to help in risk stratification.”

The phase III PRESTO trial included patients with histologically confirmed prostate adenocarcinoma with previous radical prostatectomy, subsequent biochemical recurrence, and a minimum PSA of 0.5 ng/mL, with a PSA doubling time ≤9 months at the time of study entry.

From 2017 to 2022, a total of 503 patients were randomly assigned 1:1:1 to 52 weeks of either ADT plus apalutamide; ADT plus apalutamide, abiraterone, and prednisone; or ADT alone (control). Median follow-up time was about 21 months for the primary analysis comparisons.

Most of the patients (84%) were white, 61% had a Gleason score of 6-7, and three-fourths had a PSA doubling time of 3-9 months. Time from prostatectomy to study entry was a median 4.4 years, 85% had prior radiation, and 42% had received prior ADT.

Additional findings showed a consistent improvement in PSA-PFS in both apalutamide arms among patients with a PSA doubling time of <3 months versus 3-9 months at study entry.

After treatment discontinuation, patients assigned to the ADT plus apalutamide and abiraterone arm had a numerically longer time to testosterone recovery (>50 ng/dL) versus those assigned to the control arm (4.7 vs 3.9 months, respectively), though the difference did not meet criteria for statistical significance.

Regarding safety, treatment-emergent adverse events (TEAEs) of any grade occurred in at least 91% of each treatment arm. Across the three arms, the most common TEAEs were hot flashes (78%), fatigue (55%), injection site reaction (33%), hypertension (31%), insomnia (21%), arthralgias (15%), and hyperglycemia (14%).

The most common grade ≥3 adverse event was hypertension: 7% with ADT plus apalutamide, 19% with ADT plus apalutamide and abiraterone, and 8% with ADT alone.

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