The National Comprehensive Cancer Network (NCCN) has updated its guidelines for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC), incorporating stratification based on disease volume and timing of metastases to guide systemic therapy decisions. These changes, highlighted by Rashid Sayyid and Zachary Klaassen in a UroToday discussion, reflect a more nuanced approach to treatment selection based on recent clinical trial data.
Stratification by Disease Volume and Timing
The 2024 NCCN guidelines now categorize mHSPC patients into risk groups based on disease volume (high vs. low) and timing of metastases (synchronous/de novo vs. metachronous). This stratification allows for tailored treatment recommendations that consider both prognostic factors and underlying disease biology.
- High-Volume Synchronous (De Novo) Metastases: Triplet therapy, consisting of androgen deprivation therapy (ADT) plus docetaxel with either abiraterone or darolutamide, is recommended for fit patients. Doublet therapy with ADT plus an androgen receptor pathway inhibitor (ARPI) is also an option.
- Low-Volume Synchronous or High-Volume Metachronous Metastases: Doublet therapy with ADT plus an ARPI is the preferred approach. Prostate external beam radiotherapy can be considered for select patients with low-volume disease. The guidelines also suggest considering abiraterone (based on PEACE-1 data) and docetaxel (based on STAMPEDE arm H) for systemic therapy intensification.
- Low-Volume Metachronous Metastases: ADT plus an ARPI doublet therapy is recommended.
Evidence Supporting Triplet Therapy in High-Volume Disease
Data from the ARASENS and PEACE-1 trials support the use of triplet therapy in patients with high-volume synchronous mHSPC. The ARASENS trial, which evaluated ADT plus docetaxel plus darolutamide versus ADT plus docetaxel, demonstrated a significant overall survival benefit in patients with high-volume disease (HR 0.69). Similarly, the PEACE-1 trial showed that adding abiraterone to ADT plus docetaxel improved overall survival in high-volume patients (HR ~0.7).
In contrast, both trials showed limited benefit from triplet therapy in patients with low-volume disease. In ARASENS, the hazard ratio for overall survival in low-volume patients was 0.68, but the confidence interval crossed 1, indicating a non-significant finding. The PEACE-1 trial also showed no significant overall survival benefit in low-volume patients (HR 0.83, p=0.66).
Role of Disease Timing: ENZAMET Trial
The ENZAMET trial provided insights into the impact of disease timing on treatment outcomes. The addition of enzalutamide to ADT plus docetaxel was associated with significant improvements in overall survival in patients with synchronous metastases (HR 0.73). However, no benefit was observed in patients with metachronous metastases (HR 1.1).
Prostate Radiotherapy in Low-Volume Synchronous Disease
The NCCN guidelines recommend considering radiotherapy to the prostate for patients with low-volume synchronous mHSPC, along with systemic therapy intensification using abiraterone or docetaxel. This recommendation is based on data from the STAMPEDE arm H and PEACE-1 trials.
STAMPEDE arm H, a phase 3 RCT of 2061 men with de novo mHSPC, found that radiotherapy did not improve overall survival in the overall cohort (HR 0.92). However, a subgroup analysis revealed an overall survival benefit in patients with low-volume disease (HR 0.68, 95% CI 0.52-0.90). A subsequent analysis in JAMA Oncology suggested that the survival benefit decreased as the number of bone metastases increased, with the most benefit seen in patients with three or fewer metastases.
PEACE-1 found that adding prostate radiotherapy to standard of care plus abiraterone was associated with a significant radiographic progression-free survival benefit (median 7.5 vs. 4.4 years). However, the addition of radiotherapy to standard of care alone did not show a RPFS benefit (HR 1.11). There was no overall survival benefit for the addition of prostate radiotherapy to standard of care alone or standard of care plus abiraterone.
Expanding Role of SBRT and Metastasis-Directed Therapy
The NCCN recognizes an expanding role for stereotactic body radiation therapy (SBRT) in mHSPC, particularly in patients with oligometastatic progression where PFS is the goal. SBRT to metastasis can be considered in appropriate clinical situations, with several phase II trials (e.g., ORIOLE, STOMP, SABR-COMET) demonstrating promising results.
Ongoing trials, such as PLATON, PRESTO, and START-MET, are further evaluating the role of SBRT in de novo or metachronous settings. These trials aim to clarify the optimal use of metastasis-directed therapy in mHSPC and its impact on outcomes such as CRPC-free survival, PFS, and MFS.
Personalized Treatment Paradigm
The updated NCCN guidelines emphasize a personalized treatment paradigm that considers both disease volume and timing of metastases. For low-volume de novo mHSPC, ADT plus ARPI is a clear option, with a potential role for triplet therapy in young, fit patients with bone-predominant disease. Prostate radiotherapy may also be beneficial in these patients.
For high-volume de novo mHSPC, triplet therapy is the mainstay of treatment, with consideration of prostate radiotherapy to prevent genitourinary symptoms. In low-volume relapsed mHSPC, ARPI is likely needed, and SBRT to metastatic sites is being extensively evaluated in clinical trials.
