# Apalutamide Monotherapy in Metastatic Hormone-Sensitive Prostate Cancer: A Viable Alternative to First-Generation Anti-Androgen Agents to Avoid the Flare Phenomenon and an Effective Treatment for Achieving Early PSA Response

## TL;DR

Apalutamide monotherapy effectively prevents the flare phenomenon and rapidly lowers PSA in metastatic hormone-sensitive prostate cancer patients.

## Contribution

Apalutamide monotherapy is shown as a viable alternative to first-generation anti-androgens for flare prevention and early PSA response.

## Key findings

- PSA levels decreased significantly from baseline to day 14 and further to day 28 of treatment.
- 77.8% of patients achieved >50% PSA reduction after 14 days of apalutamide monotherapy.
- Apalutamide effectively mitigates the flare phenomenon without the need for first-generation anti-androgens.

## Abstract

In this manuscript, we describe our clinical experience with patients diagnosed with metastatic hormone-sensitive prostate cancer (mHSPC) treated in first-line with apalutamide monotherapy for 14 days (to prevent the flare-up phenomenon) followed by combination therapy with apalutamide plus a gonadotropin-releasing hormone (GnRH) agonist. This treatment was continued until progression of the disease or unacceptable toxicities. We collected and analyzed serum PSA and testosterone levels at three time points: baseline (prior to starting the apalutamide monotherapy), day 14 (after 13 days of apalutamide alone), and day 28 (after 15 days of combination therapy with apalutamide and GnRH agonist), in order to assess the depth and speed of the biochemical response. Additionally, we evaluated adverse events during treatment and monitored the achievement of castration status.

Background/Objectives: Androgen deprivation therapy (ADT) is the mainstay of prostate cancer treatment, especially in advanced disease. In particular, the gonadotropin-releasing hormone agonists (aGnRH) reduce the production of gonadotropin and, therefore, of testosterone. In about 10% of patients, the non-pulsatile stimulation of GnRH receptor initially causes a surge in LH and testosterone, defined as the “flare-up phenomenon”, leading to increased bone pain, spinal cord compression, bladder outlet obstruction and cardiovascular issues. To mitigate this effect, combining a first-generation antiandrogen agent (FGA) with aGnRH is recommended. However, second-generation anti-androgens, such as apalutamide, bind selectively and irreversibly to the androgen receptor (AR), exhibiting a more efficient inhibition of the AR pathway. Methods: This is a descriptive retrospective study of 27 patients (pts) with mHSPC, treated at a single center (“Santa Maria delle Grazie” Hospital in Pozzuoli, ASL Napoli 2 Nord, Italy) between June 2022 and April 2024. Patients received apalutamide monotherapy for 14 days followed by continuous combination with aGnRH plus apalutamide. Serum PSA and testosterone levels were measured at baseline, at day 14 (after 13 days of apalutamide monotherapy), at day 28 (after an additional 15 days of apalutamide plus a aGnRH), and at day 60. Results: PSA levels decreased from a mean of 45.2 (±63.1) ng/mL at baseline to a mean of 12.6 (±23.4) ng/mL at day 14 and to 3.3 ng/mL (±6.0) at day 28 of treatment. After 14 days of apalutamide monotherapy, 21 patients (77.8%) achieved a >50% PSA reduction and 4 (14.8%) a >90% PSA reduction. The number of patients with undetectable PSA was one (3.7%) at day 14, two (7.4%) at day 28, and nine (33.3%) at day 60. The mean serum testosterone levels were 6.56 (±4.46) ng/mL at baseline, 6.58 (±4.42) ng/mL at day 14, and 2.40 (± 3.38) ng/mL at day 28. No significant difference in PSA and testosterone level reduction during treatment emerged between subgroups of patients with low- vs. high-volume disease. Conclusions: Apalutamide alone is a viable option for mitigating the flare-up phenomenon, avoiding first generation anti-androgen therapy, and it can achieve rapid and deep biochemical control.