Assessing the Prostate Cancer Treatment Paradigm: Understanding When to Intensify Treatment

When curative-intent treatment is deemed appropriate for men with clinically localized prostate cancer, some men may be cured with either radical prostatectomy (RP) or radiation therapy (RT).1,2 Despite these outcomes, many of these men will experience biochemical recurrence (BCR) within 15 years following RP (16-46%) or RT (18-36%).3 Advances in both the understanding of disease biology and ongoing clinical research have helped to evolve the management approach for men who experience BCR following definitive treatment, also known as castration-sensitive prostate cancer (CSPC).4

Educational information on non-metastatic CSPC and castration-resistant prostate cancer (CRPC).

Prostate cell growth — both malignant and non-malignant — is regulated by the androgen pathway.5 Historically, management of men with nmCSPC following “maximal local therapy” i.e., primary therapy and local salvage therapy, has not been clearly defined. Clinicians have utilized various approaches, including expectant management and both intermittent and continuous ADT.6

Unfortunately, some men with CSPC treated with androgen deprivation therapy (ADT) will eventually progress to castration resistance, which is defined as clinical and/or biochemical progression in the setting of low serum testosterone (<50 ng/dL).4 Prostate specific antigen (PSA) doubling time (PSA-DT), defined as the time in which PSA levels double, is also one of the factors that are used to predict the aggressiveness of progression.7

A challenge of disease management in nmCSPC is the significant heterogeneity of the disease biology; it is critically important to identify those who are at risk of disease progression.2

Significance of PSA-DT and BCR in prostate cancer.

PSA was identified as a biomarker to monitor disease progression for prostate cancer and was approved by the U.S. Food & Drug Administration (FDA) in 1986.8 In 1994, the FDA approved the PSA test to aid in the detection of prostate cancer in conjunction with a digital rectal exam (DRE) in men 50 years and older.8Currently PSA testing recommendations for early detection of prostate cancer depend on a variety of risk factors such as age, race and family history of prostate cancer.9

PSA-DT is considered a useful clinical metric. It provides insight to prostate cancer progression in settings such as nmCSPC, mCSPC and nmCRPC with shorter PSA-DT increasing the risk of the development of metastatic disease and death from prostate cancer.2 A short PSA-DT (12 months) after initial local therapy or following salvage local treatment is considered “high risk” BCR and is a strong predictor of progression to metastatic disease.2,10,11 Conversely, men with prolonged PSA-DT who fall into the low-risk BCR category have a similar risk of prostate cancer-specific survival compared with men with no BCR.3

While there is no consensus on the definition of high-risk BCR, professional organizations have issued guidelines based on the consolidation of evidence in the literature (Table 1).11

Table 1. Definitions of High-Risk BCR in Non-Metastatic Prostate Cancer.

XTANDI® (enzalutamide) as a treatment option in nmCSPC with high-risk BCR.

XTANDI is the first and only FDA-approved androgen receptor inhibitor (ARi) in four prostate cancer disease states.13 First approved by the FDA in 2012, XTANDI has a robust history of clinical data including nearly 7,000 patients in six clinical trials in patients with mCRPC, nmCRPC, mCSPC and nmCSPC.13

In nmCSPC with high-risk BCR, the randomized placebo-controlled Phase 3 EMBARK clinical trial showed XTANDI in combination with the GnRH therapy (leuprolide) reduced the risk of metastasis or death by 58% versus placebo plus leuprolide (Hazard Ratio [HR]: 0.42; 95% Confidence Interval [CI], 0.30–0.61; P<0.0001; number of events: 45 [12/7%]; median, months [95% CI]: not reached [NR; NR, NR]), the trial’s primary endpoint.14 [See below for trial design]. In EMBARK, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.13

Results from EMBARK supported the FDA approval of XTANDI in nmCSPC with high-risk BCR in 2023.13 With this approval, XTANDI became the first and only ARi FDA-approved for this patient population.13

Conclusion: Addressing care in nmCSPC.

Understanding PSA-DT can help to identify those at risk for disease progression and metastasis and may aid in the selection of treatment.2 For certain men with nmCSPC who are at high risk for metastasis (high-risk BCR), it may be appropriate to consider treatment with XTANDI.13

To learn more about XTANDI in nmCSPC with BCR at high risk for metastasis (high-risk BCR), visit www.XTANDIHcp.com.

Indications

XTANDI (enzalutamide) is indicated for the treatment of patients with:

• castration-resistant prostate cancer (CRPC)
• metastatic castration-sensitive prostate cancer (mCSPC)
• nonmetastatic castration‑sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)

Important Safety Information

Warnings and Precautions
Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in eight randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Ischemic Heart Disease In the combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDIversus 1.1% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo.

Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI.

Dysphagia or Choking Severe dysphagia or choking, including events that could be life-threatening requiring medical intervention or fatal, can occur due to XTANDI product size. Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. Consider use of a smaller tablet size of XTANDI in patients who have difficulty swallowing. Discontinue XTANDI for patients who cannot swallow capsules or tablets.

Adverse Reactions (ARs)
In the data from the five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to ARs were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to ARs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.

Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.

Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.

Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

Please click here for accompanying Full Prescribing Information.

© 2025 Astellas Pharma Inc. or its affiliates and Pfizer Inc. All rights reserved. MAT-US-XTD-2024-01726 02/25

REFERENCES

1 American Cancer Society. Radiation therapy for prostate cancer. Updated February 13, 2023. Accessed January 31, 2025. https://www.cancer.org/cancer/prostate-cancer/treating/radiation-therapy.html.

2 Antonarakis ES, Feng Z, Trock BJ, et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int. 2012;109(1):32-39. doi: 10.1111/j.1464-410X.2011.10422.x

3 Falagario UG, Abbadi A, Remmers S, et al. Biochemical recurrence and risk of mortality following radiotherapy or radical prostatectomy [published online September 11, 2023]. JAMA Netw Open. 2023. Accessed December 17, 2024. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2809152.

4 Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-1159.

5 Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004;25(2):276-308. doi: 10.1210/er.2002-0032.

6 Sartor O, McLeod DG, Halabi S, et al. The COMPARE Registry: design and baseline patterns of care for men with biochemical failure after definitive treatment of localized prostate cancer. Urology. 2010;75(3):623-629. doi: 10.1016/j.urology.2009.04.059

7American Cancer Society. Cancer glossary: PSA doubling time (PSADT). Accessed July 12, 2023. https://www.cancer.org/cancer/understanding-cancer/glossary/glossary/p/psa_doubling_time.html

8 National Cancer Institute. Prostate-specific antigen (PSA) test. Updated March 11, 2022. Accessed April 12, 2023. https://www.cancer.gov/types/prostate/psa-fact-sheet.

9American Cancer Society. American Cancer Society recommendations for prostate cancer early detection. Updated November 22, 2023. Accessed May 14, 2024. https://www.cancer.org/cancer/prostate-cancer/detection-diagnosis-staging/acs-recommendations.

10 Freedland SJ, Humphreys EB, Mangold LA, et al. Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. J Clin Oncol. 2007;25(13):1765-1771. doi: 10.1200/JCO.2006.08.0572.

11 Virgo KS, Rumble RB, de Wit R, et al. Initial management of noncastrate advanced, recurrent, or metastatic prostate cancer: ASCO guideline update. J Clin Oncol. 2021;39(11):1274-1305. doi: 10.1200/JCO.20.03256.

12 American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO). Salvage therapy for prostate cancer: AUA/ASTRO/SUO guideline (2024). Published 2024. Accessed June 4, 2024. https://www.auanet.org/guidelines-and-quality/guidelines/salvage-therapy-for-prostate-cancer.

13 XTANDI. Package insert. Northbrook, IL: Astellas Pharma US, Inc; 2025.

14 Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. doi: 10.1056/NEJMoa2303974