ARPI plus ADT: Evolving strategies in mCSPC

The landscape for treating metastatic castrate-sensitive prostate cancer (mCSPC) continues to evolve rapidly, driven by emerging clinical data and advanced imaging technology. A recent Urology Times Clinical Forum in Atlanta, Georgia provided a platform for practicing urologists to discuss key issues in prostate cancer management, practice guidelines, and logistical aspects of clinical care. The gathering, hosted by Carl Capelouto, MD, of Georgia Urology, covered a range of topics from the application of treatment guidelines, patient case discussions, to administrative procedures such as surveys and data collection. What follows is a summary of the discussion.

This summary was generated by artificial intelligence and edited by humans for clarity.

During the discussion, attendees highlighted that the standard of care has definitively shifted from androgen deprivation therapy (ADT) monotherapy to combination therapy, leveraging the power of novel androgen receptor pathway inhibitors (ARPIs). The discussion, however, highlighted the clinical nuances that remain when implementing these strategies, especially concerning patient-specific disease burden, prostate size, and the role of the newest agents, such as darolutamide (Nubeqa).

The shift to combination therapy and next-generation staging

The consensus among the group was clear: initial treatment for mCSPC now mandates combination therapy (ADT plus an ARPI). Historically, treatment decisions were often segmented by disease volume, using criteria like the CHAARTED data, which categorized high volume as ≥4 bone metastases (including 1 or more axial bone lesions) or the presence of visceral metastases.

However, a major theme of the discussion was that these older criteria were based on traditional imaging—bone scans and CT scans—which are now considered largely obsolete for staging. Clinicians affirmed that they have overwhelmingly transitioned to prostate-specific membrane antigen (PSMA)-PET scanning as the standard of care for initial staging and monitoring.

This shift in imaging poses a new challenge for clinicians in the setting of long-term control. Although most practitioners now utilize annual PET scans, a question was raised regarding the justification for repeated advanced imaging in a patient with a stable, undetectable PSA level after initial treatment. The response was that compelling clinical data demonstrates that radiographic progression can occur without corresponding PSA progression. Physicians must remain vigilant and push back against insurance barriers that are increasingly challenging the use of PSMA-PET scans, recognizing that earlier detection of progression via advanced imaging is clinically critical.

Addressing clinical complexity: Example patient scenarios

The panel delved into practical, complex patient scenarios where the integration of systemic and local therapies is paramount.

Managing oligometastatic disease and outlet obstruction. The discussion affirmed that for patients presenting with oligometastatic disease (e.g., low-volume nodal disease or a limited number of bone metastases), treating the primary prostate tumor with radiation is generally supported by clinical evidence, such as the STAMPEDE data.

A hypothetical case was presented to explore the challenges of local therapy in a patient with oligometastasis and a very large prostate (e.g., 120 grams). The core clinical challenge is that subjecting a patient with a large gland to prostate radiation risks severe post-treatment urinary symptoms due to damage to the obstructing tissue. The clinical recommendation emphasized that a de-obstructing procedure to address the benign prostatic hyperplasia component is essential and must be performed before radiation.

The utility of prostate arterial embolization (PAE) was discussed as a potential procedure for debulking a large gland prior to radiation, offering a less invasive option than prostatectomy and potentially moving patients to definitive radiation therapy sooner. However, it was cautioned that PAE is not well-suited for patients with a significantly large, intravesical protruding median lobe. The consensus called for more aggressive pre-radiation evaluation, including AUA symptom scores and cystoscopy, to proactively manage potential bladder outlet issues.

The established ADT monotherapy responder. Another scenario addressed the challenge of a patient already on ADT monotherapy for an extended period (5 to 8 years) with an undetectable and stable PSA, a situation often inherited by newer urologists. Although dual therapy is the new standard of care, the rationale for adding an ARPI to this subset of stable, long-term responders is unstudied. The panel acknowledged that some patients appear to experience a "burn out" of their cancer, remaining undetectable for years even after stopping ADT. This highlights the need for shared decision-making with the patient, balancing the proven efficacy of combination therapy vs a reluctance to change an apparently successful, long-established regimen.

Clinical data on darolutamide in mCSPC

The central focus of the clinical forum was the efficacy of darolutamide, primarily supported by the ARANOTE study. This placebo-controlled trial enrolled over 600 patients to compare darolutamide plus ADT vs ADT alone. The study, while utilizing older imaging methods (CT and bone scan), delivered highly impressive outcomes that reinforce the role of novel ARPIs.

Radiographic and PSA progression data

Darolutamide demonstrated an 18% difference in radiographic progression-free survival at 24 months compared with placebo, with the Kaplan-Meier curves continuing to separate beyond that time point. This long-term disease control is a dramatic improvement over historical benchmarks, where patients often progressed within 2 years.

Data on time to progression to castration-resistant prostate cancer (CRPC) was deemed "dramatic.” At the 39-month follow-up, the median time to CRPC had not been reached in the darolutamide group, whereas 80% of the placebo group had progressed to castrate resistance.

The response measured by PSA was equally compelling. Up to 39 months, nearly 80% of patients on the darolutamide-ADT combination had not experienced PSA progression, compared with only 30% on ADT alone. Furthermore, two-thirds of patients on the darolutamide arm achieved an undetectable PSA (defined as <0.2 ng/mL in the study), whereas 72% of the placebo patients never reached that level.

Although overall survival (OS) data was considered "immature" (the median had not been reached at 39 months), the panel expressed confidence that the clear delay in CRPC and radiographic progression logically implies an eventual increase in OS.

A significant advantage of darolutamide in the context of other ARPIs is its expected impact on quality of life. The specific adverse event (AE) profile, particularly regarding central nervous system AEs like fatigue, is considered a key differentiating factor, making it an attractive treatment option for long-term mCSPC management.

In conclusion, the Clinical Forum highlighted that the management of mCSPC is defined by early, aggressive combination therapy, guided by sophisticated imaging. Darolutamide, supported by robust data demonstrating impressive delays to CRPC and PSA progression, is well-positioned as a critical component of this new, effective standard of care.