ARANOTE Features Significant rPFS Benefit of Darolutamide/ADT in mHSPC

Vinay Minocha, MD

Staff Physician

University of Miami Health System

Coral Springs, FL

CASE SUMMARY

Initial Presentation

• A 67-year-old man presented with urinary retention, fatigue and decreased appetite.

Patient History, Lifestyle and Clinical Workup

• History of hypertension and hyperlipidemia, both well controlled with medication
• No family history of prostate cancer
• Widower, works full time as a commercial real estate broker, active, and very involved in his grandchildren’s activities
• Transrectal ultrasonography and biopsy revealed adenocarcinoma of the prostate gland, Gleason score 8 [4+4] with disease in 10/12 cores
• Prostate-specific antigen (PSA), 150 ng/mL; hemoglobin, 9.7 g/dL; absolute neutrophil count, 1.9

Initial Diagnosis and Treatment

• Patient was diagnosed with localized high-grade prostate cancer.
• He underwent robotic radical prostatectomy with subsequent PSA decrease (0.2 ng/mL).
• CT and bone scans showed no residual disease.
• Thirteen months after initial diagnosis – recurrence of disease

Presentation at Recurrence

• Asymptomatic, ECOG performance status: 0
• Routine follow-up:
  • PSA, 35 ng/mL; hemoglobin, 10.3 g/dL; absolute neutrophil count, 1.6
  • Imaging with CT and bone scan showed 3 metastatic bone lesions (2 in pelvis, 1 in S1 vertebrae)

Diagnosis of Recurrence

• The patient was diagnosed with metastatic prostate cancer.
• Germline and somatic genetic testing were negative.
• He was referred to a medical oncologist.
• Therapeutic options (including bimodal and trimodal regimens) were reviewed with the patient as part of shared decision making.
• He wishes to pursue an aggressive treatment approach but would prefer to receive oral treatment and minimizing adverse events (AEs) is very important to him.

Targeted Oncology: What recent relevant data are there for a patient such as this?

Vinay Minocha, MD: The ARANOTE study [NCT04736199] was recently published. It's a study of darolutamide [Nubeqa] and androgen deprivation therapy [ADT] for metastatic hormone-sensitive prostate cancer [mHSPC]. The eligibility was patients who had confirmed metastatic prostate cancer, ADT plus or minus first generation antiandrogen less than 12 weeks before randomization, and no prior second-generation androgen receptor inhibitors [ARIs], investigational ARI, chemotherapy, or immunotherapy for prostate cancer was given in this trial. Patients had an ECOG performance status of 0 to 2, and they had adequate organ function. They were randomly assigned in a 2:1 fashion to darolutamide 600 mg twice a day plus ADT vs placebo plus ADT.^1,2

The data cut off was June 7, 2024, and the primary end point was radiographic progression-free survival [rPFS] by central blinded review. Secondary end points in this trial were overall survival [OS], time to initiation of subsequent anticancer therapy, time to metastatic castration-resistant prostate cancer [mCRPC], time to PSA progression, rates of undetectable PSA, time to pain progression, and safety.

The baseline characteristics in this trial included 30% Asian patients and 10% Black patients [in both arms, but overall, the characteristics] were pretty similar across arms. Metastases were de novo and high volume in about 70% of patients [in both arms], representative of other trials. In the control arm, 70% had high volume disease and 45% had ECOG performance status of 0. It’s [no longer] standard of care for patients who have performance status of 0 to not have some other ARI. I wanted to point that out, but it seemed to be otherwise well balanced.

What was the efficacy in the ARANOTE trial?

The rPFS showed an increase in the darolutamide plus ADT arm of 70.3% vs 52.1% and that was statistically significant. It significantly reduced the risk of radiologic progression or death by 46% with approximately 25-month follow-up [HR, 0.54; 95% CI, 0.41-0.71; P < .0001]. Interestingly, patients in the darolutamide arm did not reach a median rPFS [vs a median rPFS of 25.0 months with placebo].

There was consistent benefit of darolutamide across all subgroups. In particular, looking at disease volume, those with low volume disease seemed to have much more benefit compared with high volume disease of darolutamide and ADT.

The secondary efficacy end point of OS was favoring darolutamide [HR, 0.81; 95% CI, 0.59-1.12]. The OS data were immature, not reached in either arm. The time to mCRPC was improved with 60% reduction [with darolutamide (HR, 0.40; 95% CI, 0.32-0.51)]. Time to pain progression also had 28% advantage in the darolutamide arm [HR, 0.72; 95% CI, 0.54-0.96]. Darolutamide showed a higher rate of less than 0.2 ng/mL PSA [at 62.6% vs 18.5%], and delayed time to PSA progression [HR, 0.31; 95% CI, 0.23-0.41].

How did patients with mHSPC do as far as toxicities with darolutamide?

Looking at the treatment-emergent AEs, it seemed that, as expected, darolutamide has mildly increased—but not significantly over placebo—any-grade AEs [91.0% vs 90.0%]. In terms of grade 5 AEs, interestingly, placebo had a bit more [4.7% vs 5.4%]. [Rates of] AEs were similar between treatments for grade 3 or 4 AEs [30.8% vs 30.3%]. The most common AEs were generally similar between both groups, including fatigue.

_References:

_{1. Saad F, Vjaters E, Shore ND, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. Ann Oncol. 2024;35(suppl 2):1-72. doi:10.1016/annonc/annonc1623}

_{2. Saad F, Vjaters E, Shore N, et al. Darolutamide in combination with androgen-deprivation therapy in patients with metastatic hormone-sensitive prostate cancer from the phase III ARANOTE trial. J Clin Oncol. 2024;42(36):4271-4281. doi:10.1200/JCO-24-01798}