SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. The American Cancer Society estimates that in the United States, about 313,780 new cases of prostate cancer will be diagnosed in 2025 and 35,770 men will die of the disease.
The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide), or with second generation Androgen Receptor Pathway Inhibitors (ARPIs), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide), ERLEADA® (Apalutamide) and NUBEQA® (Darolutamide). Approximately 10-20% of patients with advanced prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis.
Evidence from clinical trials indicates treatment intensification by combining ADT with ARPIs like Enzalutamide, Apalutamide, Abiraterone, or Darolutamide/chemotherapy, enhances survival in individuals with metastatic Castration-Sensitive Prostate Cancer (mCSPC). Despite clear, consensus-driven guidelines recommending treatment intensification (TI) for mCSPC, real-world data consistently show that many patients are not receiving evidence-based first-line combination therapy. This ongoing implementation gap could have significant consequences for patient survival and reflects a complex interplay of clinical, cognitive, and systemic factors.
Clinical Rationale for Treatment Intensification
Treatment Intensification, defined as the addition of an ARPI such as Abiraterone, Enzalutamide, Apalutamide, or Darolutamide, and/or Docetaxel chemotherapy to Androgen Deprivation Therapy (ADT), is supported by robust evidence from multiple Phase 3 clinical trials. These trials have demonstrated consistent Overall Survival (OS) benefits across broad patient populations with mCSPC. Median OS has improved from under three years in the pre-Treatment Intensification era to 50–60 months with modern combination approaches. As a result, major guidelines including NCCN, ASCO, and the American Urological Association now uniformly endorse Treatment Intensification as the standard of care for men with mCSPC who can tolerate it.
Real-World Underutilization of Treatment Intensification (TI)
Nevertheless, studies repeatedly show that Treatment Intensification remains underutilized in clinical practice. A recent analysis of 617 US patients with mCSPC, derived from the Adelphi Real World (ARW) of 107 US-based physicians, spanning July 2018 to January 2022, found that 69.7% of patients did not receive Treatment Intensification as initial therapy. Notably, this underuse persisted despite the availability of FDA-approved therapies and updates to treatment guidelines during this timeframe.
Similar trends have been observed in claims-based studies and physician-reported treatment patterns. A 2020 global survey revealed that 47% of patients worldwide and 36% in the U.S. did not receive Treatment Intensification. Concerningly, physician rationales often involved misinterpretations of the guidelines or concerns about treatment-related toxicity, even though trials have shown that Treatment Intensification maintains, and in some cases improves Quality of Life (QoL).
Key Findings from the ARW Survey
Physicians participating in the ARW study included medical oncologists (60.7%) and urologists (39.3%), mostly practicing in community settings. Of the 617 patients, 24.8% were African American, 8.1% were Hispanic or Latino, 58.0% were White or Caucasian, and 9.1% were of other race or ethnicity. Of note:
- Tolerability and Guidelines were top-cited reasons for both prescribing and omitting Treatment Intensification (TI).
- 64.7% of those prescribing TI cited favorable tolerability.
- 58.6% of those avoiding TI cited tolerability concerns.
- Similarly, guideline adherence was cited by 61.5% of TI users and 53.5% of non-TI users, revealing considerable guideline misinterpretation.
- Disease burden influenced TI use. Patients with higher PSA levels, Gleason grade, and high-volume disease were more likely to receive TI. For instance:
- PSA ≥75% reduction goals were associated with increased TI use (OR = 1.63).
- High PSA levels were a driver for 39% of TI prescribers vs. 18.4% of non-TI prescribers (P < .001).
- Guideline awareness was a significant predictor. Physicians who explicitly cited guidelines were more than three times as likely to prescribe TI (OR = 3.46; P = .01).
- Misconceptions persist. Among patients who did not receive ARPIs, 31.4% of physicians cited a lack of perceived clinical trial evidence supporting survival benefits, despite level-one data to the contrary.
- PSA targets may be misaligned. Many physicians aim for a 50% PSA reduction or PSA levels around 2.0 ng/mL, far above the <0.2 ng/mL level retrospectively linked to better outcomes. This disconnect may influence decision-making and undervalue the full benefits of TI.
- Treatment access and Reimbursement. The physicians reported that only 4.9% of patients were not prescribed the treatment due to insurance coverage limitations. This suggests that access to the treatment, based on insurance, is not a major barrier to treatment.
Barriers beyond Clinical Characteristics
Contrary to initial hypotheses, access and reimbursement were infrequently cited as barriers. Only 4.9% of physicians indicated that insurance coverage prevented Treatment Intensification use. Furthermore, treatment decisions were rarely driven by patient preferences or behavior. Instead, the dominant theme is knowledge gaps in guideline familiarity, evidence interpretation, and understanding of Treatment Intensification’s impact on QoL and toxicity. Many physicians appear to base decisions on outdated assumptions or incomplete reading of the literature.
Toward Better Implementation: The Role of Education
Researchers argue that continued education for both clinicians and patients is essential. Oncologists often treat multiple malignancies and may struggle to stay current. Urologists, who balance surgical and medical roles, face similar constraints. Accessible continuing medical education (CME) programs and direct patient education may help address this disconnect.
Encouragingly, recent data from the Flatiron Health EHR database suggest progress. As of early 2025, 76.8% of patients treated in large academic and community oncology centers were receiving Treatment Intensification. However, questions remain about uptake in smaller or more rural practices.
Conclusion and Call to Action
This study reinforces the importance of bridging the gap between evidence and practice. Although Treatment Intensification in mCSPC is backed by compelling evidence and endorsed by all major guidelines, many patients continue to receive suboptimal therapy due to misconceptions and outdated practice patterns.
Key takeaways for clinicians:
- Treatment Intensification is the standard of care in eligible patients with mCSPC, across disease volumes and PSA levels.
- Clinical trials consistently show Treatment Intensification improves OS without compromising QoL.
- Misinterpretation of guidelines and concerns over tolerability remain major barriers.
- Improved education and dissemination of trial data are critical to closing the gap.
Addressing these issues is essential to ensure all patients with mCSPC receive life-prolonging therapies in line with current evidence and best practice.
Physician Reasons for or Against Treatment Intensification in Patients With Metastatic Prostate Cancer. Agarwal N, George DJ, Klaassen Z, et al. JAMA Netw Open. 2024;7(12):e2448707. doi:10.1001/jamanetworkopen.2024.48707
