Intensive testosterone-blocking therapy delays prostate-specific antigen progression in BRPC

A 52-week course of intensified androgen-deprivation therapy (ADT) appears to extend prostate-specific antigen progression-free survival (PSA-PFS) in patients with biochemically recurrent prostate cancer (BRPC) compared with ADT alone, without prolonging time to testosterone recovery, according to the phase III open-label PRESTO trial.

At the first interim analysis, the primary endpoint of PSA-PFS was significantly longer in the experimental arms that included patients who received either apalutamide or apalutamide plus abiraterone acetate and prednisone (AAP) in addition to a backbone ADT than in the control arm that involved patients who received ADT alone.

The median PSA-PFS was 24.9 months in the ADT–apalutamide arm vs 20.3 months in the ADT-alone arm (hazard ratio [HR], 0.52, 95 percent confidence interval [CI], 0.35–0.77; p=0.00047) and 26.0 months in the ADT–apalutamide–AAP arm vs 20.0 months in the ADT-alone arm (HR, 0.48, 95 percent CI, 0.32–0.71; p=0.00008). [J Clin Oncol 2024;doi:10.1200/JCO.23.0115]

Time to testosterone recovery (>50 ng/dL) after treatment cessation did not differ across the three treatment arms. The median recovery time was slightly longer in the ADT–apalutamide–AAP arm than in the control arm (4.7 vs 3.9 months), but the difference was not significant.

“[PRESTO] adds to a growing body of evidence in favour of more intensive testosterone-blocking therapy in patients with higher-risk prostate cancer,” said lead investigator Prof Rahul Aggarwal of the University of California San Francisco in California, US.

“The addition of apalutamide to ADT should be considered in patients with high-risk BRPC,” Aggarwal added.

Problematic

In an accompanying editorial, Dr Daniel Childs of Mayo Clinic in Rochester, Minnesota, US, and his colleagues had misgivings about the use of PSA-PFS as the primary endpoint in PRESTO, calling it “problematic.” [J Clin Oncol 2024;doi:10.1200/JCO.23.0115]

“Rises in PSA are not currently well established as a surrogate for the gold standard endpoint of OS… The definition of PSA progression used in this study (PSA rise >0.2 ng/mL) is not at a typical threshold for obtaining conventional imaging or reinitiating systemic therapy in routine clinical practice,” Childs and colleagues wrote. [N Engl J Med 2012;367:895-903]

“Granted, we have now entered an era with better molecular imaging, such that early rises in PSA have become more relevant, but research in this area is still ongoing… For now, it is notable yet unsurprising that intensified ADT delayed median PSA progression by the order of 4-6 months,” they continued.

Accordingly, Childs and colleagues expressed skepticism about the adoption of intensified ADT based on PRESTO’s primary endpoint, asking whether delaying PSA rise by a median of 4 months would be worth a year of added expense and the potential for adverse events.

“It remains unclear whether [a prolonged PSA-PFS] equates to more time off treatment and delay of metastasis,” they noted.

Meaningful intermediate clinical endpoint

As an intermediate clinical endpoint (ICE), the proportion of patients with a sustained treatment-free interval and eugonadal testosterone after therapy interruption would provide a better picture of how well treatments are working in future studies, according to Childs and colleagues.

Being used in the phase II A-DREAM trial in which treatment break is evaluated in men with exceptional response to intensified ADT for metastatic hormone-sensitive prostate cancer, such an “endpoint is highly patient-centric and meaningful since less time on treatment promises fewer treatment-related side effects, better quality of life, and less detrimental long-term health consequences of chronic testosterone suppression,” they said. [N Engl J Med 2012;367:895-903; JAMA 2005;294:433-439; J Clin Oncol 2013;31:2029-2036]

Childs and colleagues stressed that the BRPC population consists mainly of asymptomatic men who are likely to live years without experiencing any disease-related consequences. In these cases, the potential toxicity of therapy could exacerbate pre-existing comorbidities and even elevate the risk of nonprostate cancer mortality, they added.

“[T]here should be a high bar for declaring benefit of treatment intensification and low tolerance for additional toxicity, physical or otherwise. The best endpoint for BRPC is not clear, but we should remember that when diseases move slowly, we too should exercise patience in waiting for the most meaningful results,” they said.

PRESTO

PRESTO included 503 BRPC patients with PSA doubling time of ≤9 months, three-fourths of whom had a PSA doubling time of 3-9 months. The median PSA at baseline was 1.8 ng/mL. The majority of the population were White (84 percent) and had a Gleason score of 6-7 (61 percent). The median follow-up duration for the primary analysis was 21 months.

The patients had a median of 4.4 years between their prostatectomy and enrolment in the study. Among them, 85 percent had previously undergone radiation therapy and 42 percent had received ADT.

In terms of safety, treatment-emergent adverse events (TEAEs) of any grade occurred in at least 91 percent of patients in each treatment arm. hot flashes (78 percent) and fatigue (55 percent) were the most frequent TEAEs overall, followed by injection site reaction (33 percent), hypertension (31 percent), insomnia (21 percent), arthralgias (15 percent), and hyperglycaemia (14 percent).

Hypertension was the most common grade ≥3 adverse event, occurring in 7.5 percent in the ADT-alone arm, 7.4 percent in the ADT–apalutamide arm, and 18 percent in the ADT–apalutamide–AAP arm.