Turkish Oncologists Outline a Roadmap for Newly Diagnosed Stage 4 Prostate Cancer

Prostate cancer is one of the most common cancers in men. Approximately 1.5 million people are diagnosed each year, and around 400,000 die from it. Its stages are critical in determining the course of disease and treatment options.

Metastatic Castration-Sensitive Prostate Cancer (mCSPC) is an advanced stage in which prostate cancer has spread to other parts of the body but still responds to androgen-deprivation therapy (ADT, suppression of male hormones). Approximately 10-20% of prostate cancer patients are diagnosed at this stage, underscoring the seriousness of this form of disease and the need for treatment.

This article was written by Prof. Dr. Yüksel Ürün and Assoc. Prof. Dr. Emre Yekedüz, two internationally recognized Turkish oncologists with extensive experience in genitourinary cancers. Their broad experience and in-depth knowledge offer a critical perspective on current developments and potential future strategies in prostate cancer treatment. In the following sections, the authors explain key concepts and drugs, including androgen-deprivation therapy (ADT), docetaxel, and androgen receptor pathway inhibitors (ARPIs). They discuss combination therapies and monotherapy used for metastatic solid tumors in terms of their effects and potential in prostate cancer. They also examine findings from trials such as PEACE-1 and ARASENS, how these studies have transformed mCSPC treatment, and their effects on treatment standards. Current practice, combinations, and individualized approaches in mCSPC are discussed in detail.

Are We Ready to Personalize Treatment for Metastatic Castration-Sensitive Prostate Cancer?

June 15, 2023, ASCO Daily News

Dr. Emre Yekedüz and Dr. Yüksel Ürün

Treatment of metastatic castration-sensitive prostate cancer (mCSPC) has evolved dramatically in recent years. Combining androgen-deprivation therapy (ADT) with docetaxel and/or next-generation androgen receptor pathway inhibitors (ARPIs) has become standard treatment.

Selecting mCSPC Treatment: History, Factors, and Standard Care

In oncology, combination therapies—particularly those with different mechanisms that do not increase toxicity—are key to success. The BEP regimen used for testicular germ cell tumors is a notable example of successful treatment of metastatic solid tumors. However, monotherapy can also be highly successful when there is a targetable oncogenic driver, as with imatinib in chronic myeloid leukemia and gastrointestinal stromal tumors.

Current mCSPC guidelines are based on studies showing that ADT combined with docetaxel or ARPIs is more effective than ADT alone. Trials such as PEACE-1 and ARASENS also investigate triplet therapy. However, older age, comorbidities, and the lack of reliable biomarkers complicate treatment selection. Terms such as "high risk" and "high volume" help classify trial participants, but biomarkers are still needed to guide treatment. The role of alterations in BRCA1 and BRCA2—genes recommended for routine evaluation in locally advanced and metastatic disease—remains incompletely understood in mCSPC.

Many new mCSPC regimens are available. Without a clear contraindication to ARPIs or chemotherapy, treating patients with ADT monotherapy alone would be inappropriate. Every patient differs, however, so a universal recommendation is impossible; treatment must be individualized. Identifying patients whose initial intensive treatment can be reduced is particularly important. Observation or ADT alone may be appropriate for asymptomatic mCSPC patients with a life expectancy of 2 years or less. In a real-world study by Swami and colleagues, tumor SPOP mutations were associated with improved outcomes in de novo mCSPC patients receiving ADT plus ARPIs, but no such association was found with ADT plus docetaxel.

Given the many new treatment regimens available for mCSPC, treating patients with ADT monotherapy would be wrong without a definite contraindication to ARPIs or chemotherapy.

Abbreviations: ADT, androgen-deprivation therapy; N/A, data not yet mature; NR, median not reached; NSAA, nonsteroidal antiandrogen; OS, overall survival; rPFS, radiographic progression-free survival; RT, radiotherapy; SOC, standard of care; VM, visceral metastases.

Docetaxel in mCSPC Treatment

A pivotal study in 2004 introduced docetaxel into treatment for metastatic castration-resistant prostate cancer (mCRPC) . About 10 years later, the GETUG-AFU-15, CHAARTED, and STAMPEDE trials introduced it into metastatic castration-sensitive prostate cancer (mCSPC) treatment. A meta-analysis pooling these three trials found that docetaxel increased 4-year overall survival (OS) in mCSPC by 9%. Hormonal therapies remain the cornerstone of prostate cancer treatment, while chemotherapy may not suit every patient. Combining ADT with drugs such as abiraterone acetate, enzalutamide, apalutamide, or rezvilutamide improves overall survival compared with ADT monotherapy, making ADT plus ARPIs standard practice in mCSPC.

With 2 active treatment approaches, we naturally ask whether 1 + 1 > 2. We therefore wondered about the combined efficacy of docetaxel and ARPIs with ADT. PEACE-1 and ARASENS allowed us to assess this triplet. The main hypothesis in PEACE-1 involved adding abiraterone acetate to standard care, while that in ARASENS involved adding darolutamide. However, neither trial's design allows the contribution of docetaxel to be evaluated, and the lack of an ADT plus ARPI arm in both trials has attracted criticism.

Adding Abiraterone and Darolutamide to Standard Care

The initial PEACE-1 analysis presented by Fizazi and colleagues at the 2021 ESMO Congress showed an OS advantage from adding abiraterone to standard care in patients receiving ADT alone and in those receiving ADT plus docetaxel. More detailed subgroup analysis showed greater benefit in patients with high metastatic burden. An update presented by Mourey and colleagues at the 2023 ASCO Genitourinary (GU) Cancers Symposium examined age, finding that patients aged 70 or older benefited less from triplet therapy than younger patients.

In ARASENS, first presented by Smith and colleagues at the 2022 ASCO GU Cancers Symposium, adding darolutamide to ADT plus docetaxel provided a 12% OS benefit over 4 years. Although tumor volume was not assessed initially, the benefit was more pronounced in patients metastatic at diagnosis. Hussain and colleagues presented updated results at the same symposium in 2023. Triplet therapy improved OS in high-risk, high-volume, and low-risk groups, but no significant difference was found in the low-volume group. PEACE-1 and ARASENS did not compare the doublet treatments or establish whether triplets were superior to ADT plus ARPI combinations. It would therefore be wrong to assume triplet regimens are more effective than ADT plus ARPIs.

Our highest priority should therefore be to remove barriers to medical access and reach more patients so they can share in these remarkable results.

Final Thoughts

It is clear that direct comparisons between studies are inappropriate. Examining each trial separately shows that their patient populations were not the same. We emphasize that treatment access is a major problem for real-world patients and that many with mCSPC still receive ADT alone. Removing access barriers and reaching more patients so they can share in these remarkable results must therefore be our top priority. In daily practice, what are we doing, in light of recent research, to recognize the value of individualized care and coordinate decision-making with the patient?

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