{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T15:42:29Z","timestamp":1785166949587,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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 \u201cflare-up phenomenon\u201d, 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 (\u201cSanta Maria delle Grazie\u201d 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 (\u00b163.1) ng\/mL at baseline to a mean of 12.6 (\u00b123.4) ng\/mL at day 14 and to 3.3 ng\/mL (\u00b16.0) at day 28 of treatment. After 14 days of apalutamide monotherapy, 21 patients (77.8%) achieved a &gt;50% PSA reduction and 4 (14.8%) a &gt;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 (\u00b14.46) ng\/mL at baseline, 6.58 (\u00b14.42) ng\/mL at day 14, and 2.40 (\u00b1 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.<\/jats:p>","DOI":"10.3390\/cancers17152573","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T10:50:21Z","timestamp":1754391021000},"page":"2573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["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"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7430-001X","authenticated-orcid":false,"given":"Gaetano","family":"Facchini","sequence":"first","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6435-8522","authenticated-orcid":false,"given":"Andrea","family":"D\u2019Arienzo","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"},{"name":"Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8598-0323","authenticated-orcid":false,"given":"Antonella","family":"Nicastro","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"},{"name":"Department of Precision Medicine, The University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiano","family":"Flauto","sequence":"additional","affiliation":[{"name":"Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michela","family":"Izzo","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6397-086X","authenticated-orcid":false,"given":"Liliana","family":"Montella","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Riccardo","sequence":"additional","affiliation":[{"name":"Urology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Maria","family":"Fusco","sequence":"additional","affiliation":[{"name":"Urology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Trama","sequence":"additional","affiliation":[{"name":"Urology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni Di","family":"Lauro","sequence":"additional","affiliation":[{"name":"Urology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe Di","family":"Costanzo","sequence":"additional","affiliation":[{"name":"Radiology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Giacoma","family":"Tucci","sequence":"additional","affiliation":[{"name":"Radiology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Iasiello","sequence":"additional","affiliation":[{"name":"Radiology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Di Lorenzo","sequence":"additional","affiliation":[{"name":"Clinical Pathology Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Maddaluno","sequence":"additional","affiliation":[{"name":"Clinical Pathology Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Liguori","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita Assante di","family":"Cupillo","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Coppola","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Minissale","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa Di","family":"Nardo","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7205-5105","authenticated-orcid":false,"given":"Luigi","family":"Formisano","sequence":"additional","affiliation":[{"name":"Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, The University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0813-3126","authenticated-orcid":false,"given":"Giuliana","family":"Ciappina","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Section of Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Pisconti","sequence":"additional","affiliation":[{"name":"Oncology Unit, Ospedale San Giuseppe Moscati, Statte, 74010 Taranto, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-9148","authenticated-orcid":false,"given":"Massimiliano","family":"Berretta","sequence":"additional","affiliation":[{"name":"Division of Oncology, Azienda Ospedaliera Universitaria \u201cGaetano Martino\u201d Hospital, 98124 Messina, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Messina, 98122 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9244-8263","authenticated-orcid":false,"given":"Chiara","family":"Barraco","sequence":"additional","affiliation":[{"name":"Oncology Complex Unit, Santa Maria delle Grazie Hospital, ASL NA2 NORD, 80078 Pozzuoli, Italy"},{"name":"Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.eururo.2019.08.005","article-title":"Recent Global Patterns in Prostate Cancer Incidence and Mortality Rates","volume":"77","author":"Culp","year":"2020","journal-title":"Eur. 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