Considering the Treatment of mHSPC with Oral Therapies

Oral therapies have become pivotal in treating metastatic prostate cancer, offering effective options with manageable adverse events. Jahan Aghalar, MD, a medical oncologist/hematologist at New York Cancer and Blood Specialists, highlighted treatment optimization and clinical trial insights in a live Community Case Forum eventinNew Jersey with Regional Cancer Care Associates. Aghalar discussed the NCCN guidelines for managing recurrent disease, as well as landmark trials that demonstrated survival benefits and shaped current treatment paradigms.

CASE SUMMARY

Initial presentation

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

Patient history, lifestyle, and clinical work-up

• History of hypertension and hyperlipidemia, both well controlled with medication
• No family history of prostate cancer
• The patient is a widower who works full time as a commercial real estate broker, is active, and is very involved in his grandchildren’s activities.
• Transrectal ultrasound 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, 1900/μL

Initial diagnosis and treatment

• The patient was diagnosed with localized high-grade prostate cancer.
• He underwent robotic radical prostatectomy with subsequent PSA decrease (<0.1 ng/mL).
• CT and bone scans showed no residual disease.

Thirteen months after initial diagnosis – recurrence of disease

Presentation at recurrence

• Asymptomatic
• ECOG performance statis: 0
• Routine follow-up
  • PSA, 35 ng/mL; hemoglobin 10.3 g/dL; absolute neutrophil count, 1600/μL
  • Imaging with CT and bone scan showed multiple enlarged retroperitoneal lymph nodes and 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 wished to pursue an aggressive treatment approach but would prefer to receive oral treatment and minimizing adverse events is very important to him.

Targeted Oncology: What do the NCCN guidelines recommend for a patient such as this with metastatic prostate cancer?

Jahan Aghalar, MD: Prostate cancer has become a bit more complicated than how it was 15 years ago. We now have patients who are considered to have high-volume disease, low-volume disease, and synchronous metastases, also known as de novo metastatic disease vs metachronous metastases. Our patient has low-volume, metachronous metastases. According to the NCCN guidelines, there are now 3 Category 1 recommended oral agents to use, in addition to the usage of primary androgen deprivation therapy [ADT]: abiraterone [Zytiga], apalutamide [Erleada], and enzalutamide [Xtandi].¹ Then there's another recommended regimen, darolutamide [Nubeqa], which was given a Category 2B recommendation. Generally speaking, as per the algorithm, we generally treat these patients until there is intolerable toxicity or progression, and then we move on to further lines of therapies in the castration-resistant setting.

Which landmark trials led to approval of oral drugs in addition to chemotherapy in patients with metastatic hormone-sensitive prostate cancer (mHSPC)?

In 2013 and 2014, the LATITUDE study [NCT01715285] showed the benefit of adding abiraterone.² From 2014 through 2017, the ENZAMET trial [NCT02446405] was performed, and that showed the benefit in adding enzalutamide with or without chemotherapy.³ Docetaxel plus ADT, based off the [CHAARTED trial; NCT00309985], showed an OS benefit in 2015 to 2016.⁴ The TITAN study [NCT02489318], a similar trial, looked at apalutamide and showed a benefit.⁵ ARCHES [NCT02677896] was another trial that used enzalutamide. Then in 2018, abiraterone was approved for mHSPC. Shortly after that, apalutamide was approved. Shortly after that, enzalutamide was approved within this clinical context.

More recently, darolutamide came into the sphere, initially through the data from the ARASENS trial [NCT02799602] using triplet therapy of darolutamide, docetaxel, and ADT in comparison with ADT plus docetaxel alone. PEACE-1 [NCT01957436] was a study that looked at whether or not there's any added benefit adding abiraterone to docetaxel and ADT; that was also a positive trial.⁶ Then the latest trial, ARANOTE [NCT04736199], looked at using darolutamide with ADT, not necessarily requiring chemotherapy.

What were the similarities and differences among the trials you’ve discussed?

STAMPEDE [NCT00268476] and ENZAMET did allow concurrent chemotherapy. LATITUDE was just abiraterone alone. More or less, all the trials were very comparable in terms of the age of the patients, the percentage of patients who had high-volume disease, whether or not there was any OS benefit. I do want to point out that the trials that did show OS benefit, in particular were LATITUDE, STAMPEDE, ENZAMET, and TITAN.^2,3,5,7 For ARCHES and ARANOTE, their primary end points were radiographic progression-free survival and ARCHES did have an OS benefit that was statistically significant on the HR [0.66].⁸ ARANOTE, on the other hand, had an HR of 0.81, which was not statistically significant.⁹

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer; version 2.2025. Accessed July 10, 2025. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf}

_{2. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700. doi:10.1016/S1470-2045(19)30082-8}

_{3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835}

_{4. Kyriakopoulos CE, Chen YH, Carducci MA, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase III E3805 CHAARTED trial. J Clin Oncol. 2018;36(11):1080-1087. doi:10.1200/JCO.2017.75.3657}

_{5. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021;39(20):2294-2303. doi:10.1200/JCO.20.03488}

_{6. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1}

_{7. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900}

_{8. Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol. 2022;40(15):1616-1622. doi:10.1200/JCO.22.00193}

_{9. 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}