Practice-Changing Trial in Prostate Cancer Shows Benefits of Perioperative Therapy

CHICAGO — A paradigm-changing clinical trial in prostate cancer showed that perioperative apalutamide (Erleada) and androgen deprivation therapy (ADT) significantly reduced the risk of metastasis in high-risk localized disease versus ADT alone.

After more than 5 years of follow-up, metastasis-free survival (MFS) improved from 73.5% with ADT alone to 78.2% with the addition of the androgen receptor pathway inhibitor (ARPI). The combination arm also had a significantly higher rate of pathologic complete response (8.9% vs 1.0%), a second primary endpoint. Event-free survival (EFS), time to first subsequent treatment, and time to distant metastasis or death all improved with the combination.

Grade 3/4 adverse events (AEs) occurred slightly more often with the combination (39.6% vs 31.0%), driven primarily by apalutamide-associated rash, reported Mary Ellen Taplin, MD, of Dana-Farber Cancer Institute in Boston, at the American Society of Clinical Oncology (ASCO) annual meeting. The study was published simultaneously in the New England Journal of Medicine (NEJM).

“The phase III PROTEUS study, in patients with high-risk localized prostate cancer, demonstrates a breakthrough in a decades-long treatment paradigm, showing that use of apalutamide earlier can deepen responses and significantly reduce the response of cancer spreading or progressing,” Taplin said during a press briefing. “Patients treated with apalutamide plus ADT were nine times more likely to have little to no cancer remaining in the prostate after surgery, and they had a 20% reduced risk of death or metastasis. Patients treated with apalutamide plus ADT did not need subsequent therapy for a median of 5 years.”

“These results support the perioperative use of apalutamide plus ADT as a new standard of care for patients with high-risk localized prostate cancer,” she added.

In an accompanying NEJM editorial, Emmanuel Antonarakis, MD, of Masonic Cancer Center and the University of Minnesota in Minneapolis, suggested the study results could “turn [the] standard paradigm on its head,” assuming FDA approval of perioperative apalutamide-ADT.

“In the post-PROTEUS era, a patient with high-risk localized or locally advanced prostate cancer would have two broad treatment options: primary radiotherapy with 18 to 24 months of ADT, or radical prostatectomy with 12 months of perioperative ADT plus apalutamide,” Antonarakis wrote. “The use of ADT plus apalutamide would represent the first option for neoadjuvant and adjuvant systemic therapy for patients with high-risk prostate cancer, marking a watershed moment in the field.”

Patients with low-risk disease would continue to be offered prostatectomy alone, he added.

Although MFS is considered a surrogate for overall survival (OS), longer follow-up is needed to confirm that association in PROTEUS.

“If yes, that would be a game changer in the field,” Antonarakis added. “Nevertheless, perioperative treatment with ADT and apalutamide will most likely be rapidly adopted as a new standard of care for patients who select surgical management for high-risk localized prostate cancer.”

William Oh, MD, of Yale Cancer Center in New Haven, Connecticut, told MedPage Today that the trial left several questions unanswered. In particular, the study did not address how the ARPI-ADT combination compares with ADT and radiation therapy, a commonly used standard of care, or with surgery plus adjuvant therapy.

Additionally, whether the results apply to enzalutamide (Xtandi) and darolutamide (Nubeqa), remains to be seen. Oh noted that the three drugs have similar mechanisms of action but different side-effect profiles. At this point, the older ARPI abiraterone, which has a different mechanism of action, might have the most relevance with regard to discussions about alternative ARPI-ADT combinations.

“Abiraterone is now generic. It’s half the price,” Oh told MedPage Today. “Would people substitute it? I think there’s a risk with substitution, as [the four ARPIs] have different side-effect profiles.”

The general principle is to infer that the results apply to different drugs in the class, “but it’s not good practice because the data are with apalutamide,” he added.

PROTEUS had its origin in data showing that 20% of newly diagnosed localized prostate cancer has high-risk characteristics, placing the patients at increased risk of recurrence and death, despite effective curative-intent treatment options. More than half of patients with high-risk localized disease will relapse, incurring morbidity from subsequent therapy, Taplin noted.

In an effort to improve disease control, investigators enrolled 2,109 patients with high-risk localized prostate cancer and randomized them to ADT before and after surgery, paired with apalutamide or placebo. The primary endpoints were pCR/measurable residual disease (MRD) and MFS by conventional imaging, PSMA-PET imaging, or histopathology, as determined by independent review.

The trial met both primary endpoints, showing a 10-fold improvement in the odds ratio for pCR/MRD (P<0.0001) and a 20% reduction in the hazard for MFS (95% CI 0.67-0.96, P=0.02). Patients randomized to perioperative ARPI-ADT had a median EFS of 57.1 months versus 38.4 months for the control arm (HR 0.71, 95% CI 0.63-0.80, P<.0.0001), and median time to subsequent therapy almost 3 years longer (74.2 vs 41.5 months, HR 0.65, 95% CI 0.57-0.73, P<0.0001).

AEs (all grade and grade ≥3) occurred more often with ARPI-ADT but were consistent with prior studies of the therapies, said Taplin. Overall rates of treatment-emergent AEs were similar between groups (94-95%), and grade ≥3 events occurred more often with the combination (28% vs 19%).