HSPC and biochemical recurrence

Prostate cancer pathophysiology: HSPC focus

Overview of prostate cancer

In 2022, more than 1.4 million men were diagnosed with prostate cancer worldwide, with an age-standardized rate (ASR) of 29.4 per 100,000 people¹

Prostate cancer is reported to be the fifth leading cause of cancer deaths globally in men, accounting for almost 400,000 deaths in 2022, with an ASR of 7.3.¹ It is the second most commonly diagnosed cancer in men worldwide and is considered a major public health issue.^1-3 In 2024, there was estimated to be 299,010 new cases of prostate cancer in the United States, accounting for 14.9% of all new cancer cases.⁴

Well-known risk factors of prostate cancer include:

• Age^2,5
• Race²
• Comorbidities, e.g., obesity, autoimmune diseases, metabolic syndrome^2,5
• Family history^2,5
• Genetics⁵
• Hormonal factors⁶

Prostate cancer and its treatments have significant negative impact on quality of life for patients, including:

• Urinary and sexual dysfunction^7,8
• Bowel dysfunction^7,8
• Fatigue^7,8
• Psychological distress^7,8
• Complications related to treatment^7,8
• Effect on family^9,10

The impact varies depending on the disease stage, timing, and treatment used.⁸ In some cases, people with prostate cancer may choose to prioritize improved quality of life over cancer-specific survival.⁷

In the majority of people, sensitivity to androgens is lost as prostate cancer advances; prior to this stage, the cancer is castration-sensitive, androgen-responsive, or hormone-sensitive^11,12

While hormone-sensitive prostate cancer (HSPC) can be localized or metastatic, de novo metastatic HSPC (mHSPC) represents 5–10% of diagnoses and 50% of prostate cancer-related mortality globally.¹³ In Western countries, this incidence is increasing – likely explained by the adoption of new diagnostic tools able to detect metastatic prostate cancer.¹³ A US study reported that mHSPC accounts for less than 5% of the annual incidence of prostate cancer.¹⁴ In people with localized HSPC, a response to medical or surgical castration will be seen, and survival rates are higher at this stage prior to metastases (Figure 1).¹⁵ However, HSPC is likely to progress to castration-resistant stages, in which androgen sensitivity and responsiveness to treatment is lost and survival rates diminish (Figure 1).^15,16

Figure 1. Continuum of disease stages of prostate cancer. 5-year survival rates for prostate cancer (data between 2014–2020) based on SEER definitions of localized and distant prostate cancer.⁴ Data from National Cancer Institute, Cattrini et al. 2019, Teo et al. 2019, Pan et al. 2023, and Karim et al. 2025.^4,15-18 ADT, androgen-deprivation therapy; BCR, biochemical recurrence; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; nmHSPC, non-metastatic hormone-sensitive prostate cancer; SEER, Surveillance, Epidemiology, and End Results Program.

What are the mechanisms underlying progression in prostate cancer? Bertrand Tombal (Université catholique de Louvain, Brussels, Belgium) discusses the pathophysiology of prostate cancer, including the role of androgen receptors and other molecular pathways in the recurrence of disease and progression to castration-resistant states. View transcript.

Pathophysiology of prostate cancer

Prostate cancer is considered a genetically heterogeneous tumor due to the ability of the neoplastic cells to switch between different lineages and phenotypic cell states dependent on their environments.^19,20

Androgen receptor (AR) signaling and the AR pathway is central to the initial development of prostate cancer, and the AR is thought to be the primary physiological factor that determines the growth and progression of the tumor.²⁰

AR is part of the steroid hormone receptor superfamily and is a ligand-activated nuclear transcription factor that controls target gene expression.²⁰ It consists of an N-terminal domain (NTD), DNA-binding domain (DBD), hinge region, and ligand-binding domain (LBD).²⁰ AR-dependent resistance is typically rare in primary prostate cancer but it is observed in 70% of castration-resistant prostate cancer (CRPC) cases.²⁰

Interplay between the AR and other molecular pathways, including the DNA repair pathway, the PTEN/PI3K/ART/mTOR pathway, the cell cycle pathway, the Wnt pathway, and the neuroendocrine pathway, supports cancer cell survival and proliferation.²⁰

In addition, activity in the AR pathway is associated with immunosuppression, which is thought to further contribute to tumor progression.²⁰ This includes androgen signaling-induced thymic involution and inhibition of differentiation of circulating T cells in T helper type 1 cells.²⁰ An increase in presence of B cell infiltrates have also been associated with progression of prostate cancer.²⁰ The presence of immunosuppressive cells and immune checkpoint signaling can contribute toward the survival of prostate cancer cells by blocking the detection or destruction of cells by the immune system.²⁰

Pathophysiology of HSPC and further progression

In people with HSPC, the tumor is initially responsive to androgen-deprivation therapy (ADT), which suppresses testosterone to the level that would be expected if the testicles had been removed by medical or surgical castration.^20,21 Of those who receive ADT, 80–90% respond, although de novo metastatic or recurrent metastatic disease can occur in some people.^15,22

The timing to develop metastases can vary between individuals and, in some cases, patients develop metastases but continue to respond to medical or surgical castration; this disease stage is known as metastatic HSPC (mHSPC).¹⁵

However, the hormone-sensitive phase and response to ADT is usually transient in people with both localized and metastatic disease, and almost all people with HSPC will progress to ultimately develop metastatic CRPC (mCRPC).²⁰ Metastatic, treatment-resistant disease has the highest mortality, underscoring the need for accurate risk stratification and early intervention.^15,23

In 10–50% of people with prostate cancer, progression to mCRPC occurs within 3 years of diagnosis²⁴

Progression can be due to AR-dependent or AR-independent resistance mechanisms, although progression is primarily attributed to maintenance of AR signaling.²⁰

In the case of AR-dependent resistance, resistance is driven by a further mutation of the ARs, particularly in the LBD, and AR splice variant expression.¹⁹ AR-independent resistance mechanisms involve other molecular pathways, including:²⁰

• DNA damage response (DDR) pathway
• PTEN/PI3K/AKT/mTOR pathway
• Cell cycle pathway
• Wnt pathway
• TMPRSS2/ETS fusion
• Neuroendocrine pattern
• Immune system response

Understanding the pathophysiological mechanisms of progression in prostate cancer is important for effective diagnosis and management of different disease stages in the clinic.

HSPC biochemical recurrence and risk of progression

Disease progression patterns

Prostate cancer is a continuum of different disease states, and an initial diagnosis may be made when the cancer is localized, locally advanced, or metastatic.¹

Following an initial diagnosis of localized or locally advanced prostate cancer, patients may be considered either suitable (Figure 1) or unsuitable (Figure 2) for treatment with curative intent.¹ In people with non-metastatic hormone-sensitive prostate cancer (nmHSPC) considered suitable for curative-intent treatment, biochemical recurrence (BCR) may occur after definitive local therapy, and disease may ultimately progress to metastatic castration-resistant prostate cancer (mCRPC), or non-metastatic castration-resistant prostate cancer (nmCRPC) or metastatic hormone-sensitive prostate cancer (mHSPC) (Figure 1).^1,2

nmHSPC includes all people with prostate cancer who are androgen deprivation therapy (ADT)-naive and do not have evidence of metastatic disease.³

Figure 1. Disease progression patterns for localized and locally advanced prostate cancer treated with curative intent. 5-year survival rates for prostate cancer (data between 2014–2020) based on SEER definitions of localized and distant prostate cancer.⁴ Data from Mateo et al. 2019, Verry et al. 2022, Giunta et al. 2024, National Cancer Institute, Cronin et al. 2010, and Cattrini et al. 2019.^1-6 ADT, androgen deprivation therapy; BCR, biochemical recurrence; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; nmHSPC, non-metastatic hormone-sensitive prostate cancer; PSA, prostate-specific antigen; SEER, Surveillance, Epidemiology, and End Results Program.

Figure 2. Disease progression patterns for localized and locally advanced prostate cancer unsuitable for curative intent. 5-year survival rates for prostate cancer (data between 2014–2020) based on SEER definitions of localized and distant prostate cancer.⁴ Data from Mateo et al. 2019, Verry et al. 2022, Giunta et al. 2024, National Cancer Institute, Cronin et al. 2010, and Cattrini et al. 2019.^1-6 ADT, androgen deprivation therapy; mCRPC, metastatic castration-resistant prostate cancer; nmCRPC, non-metastatic castration-resistant prostate cancer; nmHSPC, non-metastatic hormone-sensitive prostate cancer; PSA, prostate-specific antigen; SEER, Surveillance, Epidemiology, and End Results Program.

BCR and disease progression

What is BCR in prostate cancer, and how can we diagnose it effectively in the clinical setting? Bertrand Tombal (Université catholique de Louvain, Brussels, Belgium) discusses the relevance of prostate-specific antigen (PSA) across prostate cancer disease states, BCR risk groups, and what they mean for patient outcomes. View transcript.

According to the 2016 EAU-ESTRO-SIOG guideline, BCR is estimated to occur in 27–53% of people with prostate cancer following definitive local therapy⁷

BCR is defined as rising serum levels of prostate-specific antigen (PSA) following primary definitive therapy and may occur prior to local recurrence or metastases.⁷ PSA is used as a marker of cancer burden in people with prostate cancer and will decrease during radical prostatectomy (RP) or radiotherapy.^1,8 However, PSA will rise again if cancer recurs, and baseline PSA level, PSA velocity, and PSA doubling time are associated with development of bone metastases and overall survival.^8,9

While RP or radiotherapy can be curative for many patients, long-term follow-up studies estimate that between 20–40% and 30–50% of people with prostate cancer may experience BCR within 10 years following RP or radiotherapy, respectively.⁷

Predicting progression

BCR and PSA levels can be predictive of disease progression, but stratification of risk is required, and their true impact on patient outcomes continues to be investigated.^10-12

There is variability in how BCR is defined according to primary treatment:

• After RP, the AUA/ASTRO/SUO 2024 guideline states that PSA >0.2 ng/mL on two consecutive measures indicates high risk for further progression¹³
• After primary radiotherapy, recommendations from the RTOG-ASTRO Phoenix Consensus Conference state PSA levels do not usually fall to zero, and so in this scenario, BCR is defined as PSA ≥2 ng/mL higher than the PSA nadir value, which has a high predictive accuracy^7,11

After RP, it has also been proposed that BCR defined as a threshold of PSA >0.4 ng/mL and increasing predicts further metastases.¹¹ However, 74% of people develop metastases within 10 years, demonstrating only a modest predictive accuracy.¹¹

The prostate-specific antigen doubling time (PSADT) is a mathematical approach that has been developed as a biomarker of prostate cancer progression.⁹ Accurate calculation of PSADT can be challenging, and useful tools such as the Memorial Sloan Kettering Cancer Center PSADT calculator are available online.¹⁴ However, such tools do not always account for measurement errors in PSADT values; therefore, steps may be needed to adjust for errors and ensure an accurate value can be calculated.¹⁴

The value of pretreatment PSADT as a prognostic factor has been evaluated in subgroups of people with prostate cancer subdivided according to whether they had “slow” or “fast” PSADT.^9,* Survival time was higher in the “slow” PSADT tumor groups compared with the “fast” PSADT groups across localized, locally advanced, and metastatic disease (p<0.01).⁹

A PSADT of 3.0 to 8.9 months has been associated with high risk of progression, leading to metastases and increased mortality.¹⁵

Optimizing BCR management

Managing BCR can be challenging as the optimal management pathway can be unclear, with numerous approaches available.⁷ In people with localized disease, prevention or delay of progression to metastatic disease states need to be balanced with negative impact of treatment on patient quality of life or overtreatment.⁷

Risk groups for biochemical recurrence

BCR does not always progress to a more advanced disease state, and there are approaches that can be used to identify risk groups¹¹

Guidelines from the EAU-EANM-ESTRO-ESUR-ISUP-SIOG and ESMO recommend a number of different management and treatment approaches for localized and locally advanced nmHSPC, and a person's risk of BCR can be used to further inform decision-making.^16-18

According to the EAU-EANM-ESTRO-ESUR-ISUP-SIOG 2024 guidelines, risk groups for BCR can be stratified into three risk groups according to PSA levels and disease stage:¹⁶

• Low-risk localized disease
• Intermediate-risk disease
• High-risk localized disease / locally advanced disease

Additionally, other risk stratification methods have been identified as clinically useful, including:

• International Society of Urological Pathology (ISUP); differentiates intermediate risk into three subgroups¹⁶
• Cambridge Prognostic Groups; uses a five-tier model taking into account PSA, ISUP, and computed tomography stage to separate both intermediate and high-risk groups into subgroups¹⁶

For detailed information on how to use these scoring systems, see risk stratification and predicting BCR.

*In the “slow” PSADT subgroup, median PSADT was 53.1, 26.6, and 9.8 months in people with local prostate cancer, locally advanced prostate cancer, and metastatic prostate cancer, respectively. In the “fast” PSADT subgroup, median PSADT was 5.2, 3.0, and 1.3 months in people with local prostate cancer, locally advanced prostate cancer, and metastatic prostate cancer, respectively.

Meet the expert

Bertrand Tombal, MD, PhD

Bertrand Tombal is Full Professor of Urology at the Université catholique de Louvain (UCLouvain) and Chairman of the Division of Urology at the Cliniques universitaires Saint-Luc in Brussels, Belgium. His interests include urinary oncology from both a scientific and medical perspective, with a particular focus on prostate and bladder cancer. During his PhD, he investigated the influence of growth factors on apoptosis in prostate cancer cells and the impact of apoptosis on growth factors. Tombal's primary focus in the medical sector is the treatment of advanced prostate cancer, mainly through hormone therapy and the development of novel biological agents, in which he is conducting multiple research investigations.

Disclosures: Tombal is an investigator and paid advisor for Amgen, Astellas, Bayer, Ferring, Janssen, Myovant, Pfizer, and Sanofi.

References

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2. Verry, 2022. Pattern of clinical progression until metastatic castration-resistant prostate cancer: An epidemiological study from the European prostate cancer registry. https://www.doi.org/10.1007/s11523-022-00899-6
3. Giunta, 2024. Pharmacological treatment landscape of non-metastatic hormone-sensitive prostate cancer: A narrative review on behalf of the meet-URO Group. https://www.doi.org/10.1016/j.critrevonc.2024.104534
4. National Cancer Institute, Cancer stat facts: Prostate cancer. https://seer.cancer.gov/statfacts/html/prost.html
5. Cronin, 2010. Definition of biochemical recurrence after radical prostatectomy does not substantially impact prognostic factor estimates. https://www.doi.org/10.1016/j.juro.2009.11.027
6. Cattrini, 2019. Current treatment options for metastatic hormone-sensitive prostate cancer. https://www.doi.org/10.3390/cancers11091355
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8. Liu, 2014. Evolving personalized therapy for castration-resistant prostate cancer. https://www.doi.org/10.7603/s40681-014-0002-5
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11. Van den Broeck, 2020. Biochemical recurrence in prostate cancer: The European Association of Urology prostate cancer guidelines panel recommendations. https://www.doi.org/10.1016/j.euf.2019.06.004
12. Van den Broeck, 2019. Prognostic value of biochemical recurrence following treatment with curative intent for prostate cancer: A systematic review. https://www.doi.org/10.1016/j.eururo.2018.10.011
13. Morgan, 2024. Salvage therapy for prostate cancer: AUA/ASTRO/SUO guideline part I: Introduction and treatment decision-making at the time of suspected biochemical recurrence after radical prostatectomy. https://www.doi.org/10.1097/ju.0000000000003892
14. Kupper, 2023. Commentary: On measurement error, PSA doubling time, and prostate cancer. https://www.doi.org/10.1016/j.gloepi.2023.100129
15. Freedland, 2007. Death in patients with recurrent prostate cancer after radical prostatectomy: prostate-specific antigen doubling time subgroups and their associated contributions to all-cause mortality. https://www.doi.org/10.1200/jco.2006.08.0572
16. Cornford, 2024. EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer-2024 update. Part I: Screening, diagnosis, and local treatment with curative intent. https://www.doi.org/10.1016/j.eururo.2024.03.027
17. Parker, 2020. Prostate cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. https://www.doi.org/10.1016/j.annonc.2020.06.011
18. Fizazi and Gillessen, 2023. Updated treatment recommendations for prostate cancer from the ESMO clinical practice guideline considering treatment intensification and use of novel systemic agents. https://www.doi.org/10.1016/j.annonc.2023.02.015

MA-MM-14238, April 2025.