In the management of metastatic hormone-sensitive prostate cancer (mHSPC), treatment intensification with androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy is typically considered within the first six months of initiating androgen deprivation therapy (ADT).¹ However, patient responses to treatment remain highly variable.¹ Although clinical trial data suggest that early absolute prostate-specific antigen (PSA) levels are predictive of long-term outcomes, evidence from real-world settings has been limited.¹ At the 2025 ASCO Annual Meeting, Dr. Michael Ong from the Ottawa Hospital Research Institute in Canada presented a multinational, prospective real-world study that provided new insight into the prognostic significance of PSA levels at 6-12 months post-treatment in men with mHSPC intensified by ARPIs.¹

The study leveraged data from the IRONMAN registry, which is a prospective, international cohort that includes over 4,600 patients with mHSPC and castration-resistant prostate cancer (CRPC).¹ The registry spans 123 active sites across 15 countries, collecting real-world data such as patient demographics, blood samples, outcomes data, and patient- and physician-reported questionnaires.¹ This study included 1,219 patients with mHSPC who were treated with ADT + an ARPI with or without docetaxel, with PSA data ≥12 months from the registry.¹ PSA values at 6 and 12 months post-ADT treatment were recorded and stratified into three groups: <0.1ng/mL, 0.10ng/mL-0.19ng/mL, and ≥0.2ng/mL.¹ Conditional time to progression-free survival (PFS) and conditional survival were evaluated across groups to examine whether absolute PSA levels at 6 and 12 months after treatment initiation could reliably stratify patient outcomes in a real-world context.¹

The median age of the study cohort was 70 years, with 75% presenting with de novo metastatic disease and 58% having high-grade tumors (Gleason score 8-10).¹ The patients were predominantly Caucasian (74%), with 8% Black, and 2% Asian.¹ Bone metastases were reported in 46% of participants, while 9% had lung metastases and 5% had liver involvement.¹ In terms of treatment, patients received ARPIs including abiraterone acetate + prednisone (44%), apalutamide (21%), enzalutamide (22%), and darolutamide (13%).¹ Additionally, 12% of the cohort received triplet therapy, comprising docetaxel alongside ADT-ARPI therapy.¹

PSA levels were assessed at 6- and 12-month timepoints to evaluate treatment response.¹ At the 6-month mark, half of the patients had PSA <0.2ng/mL (35% <0.1ng/mL and 17% between 0.1 and 0.19ng/mL), and 48% recorded PSA ≥0.2ng/mL.¹ By 12 months, two-thirds of patients had PSA <0.2ng/mL (50% <0.1ng/mL and 18% between 0.1ng/mL and 0.19ng/mL), and a third had PSA ≥0.2ng/mL.¹ Majority (82%) of patients with PSA ≥0.2ng/mL at 6 months still have detectable PSA (≥0.1ng/mL) at 12 months.¹

Stratification by 6- and 12-month PSA levels revealed marked differences in clinical outcomes.¹ In the 12-month landmark cohort, patients with PSA ≥0.2ng/mL demonstrated the lowest 3-year conditional survival, with a survival rate of 45% and a median survival of 29 months.¹ In comparison, conditional survival was 79% for those with PSA levels between 0.1ng/mL and 0.19ng/mL, and 84% for patients with PSA <0.1ng/mL.¹ A similar trend was observed for conditional PFS—patients in the ≥0.2ng/mL group had a 3-year PFS rate of 41% and a median PFS of 23 months, compared to 62% in the intermediate PSA group and 80% in the lowest PSA category.¹ These differences were statistically significant (log-rank p<0.001).¹ Comparable trends were noted in the 6-month landmark cohort.¹

Multivariable Cox regression analysis further demonstrated the prognostic value of PSA at 12 months—patients with PSA ≥0.2ng/mL had nearly a fivefold increased risk of mortality compared to those with PSA <0.1ng/mL (HR=4.85; 95% CI: 3.36-7.01), while those with PSA between 0.1ng/mL and 0.19ng/mL also showed a numerically elevated risk, though this did not reach statistical significance (HR=1.34; 95% CI: 0.80-2.20).¹ Importantly, these prognostic trends were consistent regardless of the ARPI used or whether patients received doublet therapy (ADT + ARPI) or triplet therapy (ADT + ARPI + docetaxel), reinforcing the robustness of PSA as an early predictor of long-term outcomes across treatment regimens.¹

In conclusion, this analysis of the IRONMAN registry provided real-world evidence supporting absolute PSA levels at 6-12 months following ADT initiation as a prognostic marker in mHSPC patients receiving ADT and ARPI therapy.¹ Elevated PSA levels (≥0.2ng/mL) persisting after 6-12 months of treatment identify a subset of patients with significantly worse outcomes who may benefit from further treatment intensification, including enrollment in clinical trials.¹ Conversely, patients achieving low PSA levels (<0.2ng/mL), particularly those reaching <0.1ng/mL, are associated with favorable long-term survival and may be considered for future de-intensification strategies, paving the way for more personalized and risk-adapted treatment approaches.¹

In an interview with Omnihealth Practice, Dr. Tan Chih Kiang shared insights on real-world challenges and evolving strategies in the management of metastatic hormone-sensitive prostate cancer (mHSPC).

Q1: How would you describe the burden and disease presentation of prostate cancer?

Dr. Tan: According to Malaysia’s National Cancer Registry (2017-2021), the incidence of prostate cancer rose from about 7.7 to 9.3 per 100,000 population. This trend mirrors what is observed across many parts of Asia, including regions previously considered low-risk. This increase is likely multifactorial, driven by population aging, improvements in cancer reporting, greater awareness, and more widespread prostate-specific antigen (PSA) testing.

Despite greater awareness, diagnosis remains delayed in many cases—with over 50% of patients presenting at stage IV. Many only seek medical attention after experiencing lower urinary tract symptoms such as frequency, urgency, hematuria, or incontinence, which tend to appear in more advanced stages.

Q2: Can you explain the transition from hormone-sensitive to castration-resistant prostate cancer, and how treatment response is typically monitored?

Dr. Tan: Most prostate cancers are initially hormone-sensitive, meaning they respond to lowering testosterone levels with androgen deprivation therapy (ADT) as the standard first-line treatment. However, over time (often within a year), tumor resistance develops, and the disease progresses despite castrate testosterone levels. This marks the transition to castration-resistant prostate cancer (CRPC).

In clinical practice, we monitor treatment response primarily using PSA levels. PSA is typically assessed every three months, with trends being more informative than single values. A declining PSA suggests effective control, while a consistent rise may indicate disease progression and the need to adjust therapy.

Q3: How might a defined PSA cut-off improve the way clinicians monitor and manage patients?

Dr. Tan: The IRONMAN study provided valuable insights into the prognostic role of PSA, using a cut-off of 0.2ng/mL to predict survival outcomes. However, it did not specify what clinical actions should be taken when that threshold is crossed. In practice, PSA trend over time, rather than a single absolute value, remains central to disease monitoring. Ongoing trials, including TRIPLE-SWITCH and DE-ESCALATE, are now investigating whether treatment adjustments (either intensifying or de-escalating therapy) based on the 0.2ng/mL cut-off can improve outcomes. Their results may help define a more robust, evidence-based framework for PSA-guided treatment decisions.