Exploring Treatment Strategies in High-Volume mHSPC

The widespread adoption of PSMA PET imaging has fundamentally altered the landscape of prostate cancer staging, leading to significant stage migration that complicates the application of historical clinical data. When selecting appropriate management strategies for patients with metastatic hormone-sensitive prostate cancer (mHSPC), oncologists must look beyond simple lesion counts to evaluate the clinical context and degree of concordance between imaging modalities.

Factors such as tumor burden, patient comorbidities, and potential drug interactions remain central to the decision-making process. Furthermore, recent findings from the AMPLITUDE trial (NCT04497844) highlight the growing importance of germline testing and PARP inhibitors in personalized treatment planning.

During a Case-Based Roundtable event in Warren, New Jersey moderated by Mark Stein, MD, associate professor of medical oncology, Columbia University Medical Center, Stein explored the complexities of managing prostate cancer, particularly when distinguishing between high-volume and low-volume disease in the modern imaging era.

CASE DESCRIPTION

• A 67-year-old man with an active lifestyle and no family history of prostate cancer presents with urinary retention, fatigue, and decreased appetite.
• Medical history: Hypertension and hyperlipidemia, both well controlled with medication
• Transrectal ultrasound (TRUS) and biopsy reveal adenocarcinoma of the prostate gland; Gleason score 8 [4+4] with disease in 10/12 cores
• Notable laboratory findings: prostate-specific antigen (PSA) 40 ng/mL; hemoglobin (Hb) 9.7 g/dL; absolute neutrophil count (ANC) 1.9
• PSMA-PET imaging shows no evidence of metastatic disease
• Diagnosis: localized high-grade prostate cancer
• He undergoes robotic radical prostatectomy (RP); subsequent PSA (< 0.1 ng/mL)
• Imaging: post-RP CT and bone scans show no residual disease

13 months later

• PSA 35 ng/mL; Hb 10.3 g/dL; ANC 1.6
• Imaging: PSMA-PET imaging shows multiple avid enlarged retroperitoneal lymph nodes and 3 metastatic bone lesions (2 in pelvis, 1 in S1 vertebrae).
• Asymptomatic, ECOG performance status (PS) 0
• Diagnosis: metastatic prostate cancer
• Germline and somatic genetic testing are negative.
• He is referred to a medical oncologist.
• Therapeutic options (including doublet and triplet regimens) were reviewed with the patient as part of shared decision-making.
• He prefers oral therapy and to avoid chemotherapy; minimizing adverse effects is very important to him.

Targeted Oncology: How do you decide between treatment options? What factors influence your treatment selection?

Mark Stein, MD: It’s important to note that historical stratifications for disease volume were established before the widespread use of PSMA PET imaging. This transition has led to stage migration, where PET scans may reveal more extensive disease than traditional bone or CT scans. When I evaluate a patient, I look beyond just the number of lesions to assess the clinical context. For instance, although 5 lesions on a PET scan might typically suggest a good risk, the appearance of those lesions also matters. I often pull up bone windows myself to look for sclerotic lesions and conceptualize the degree of concordance between different imaging modalities.

To determine the appropriate management, I have practical considerations that influence the decision. I evaluate the overall tumor burden and whether I consider the disease to be high or low volume. I also consider real world comorbidities, such as whether the patient is frail or has existing conditions such as diabetes, hypertension, or hyperlipidemia. Furthermore, I assess the patient’s current medications, such as atorvastatin [Lipitor], to avoid adverse drug interactions. Patient preferences also play a role in my process.

For patients with high-volume disease, the management strategy shifts compared with those who have low-volume involvement. I believe that clinical data from the pre-PSMA PET era must be applied with caution to the patients we see today. While I have used apalutamide in sensitive metastatic cases, the treatment choices I make for high-volume disease are ultimately driven by the specific disease involvement and the patient's ability to tolerate the therapy. If a patient presents with high-volume disease, we must consider how that burden changes the primary treatment end point and the necessity of more intensive intervention.

What do the NCCN guidelines suggest?

In discussing the NCCN guidelines for prostate cancer management,¹ I find it essential to review these standards as they form the foundation of our clinical approach. When I evaluate a patient, I consider their physical examination, life expectancy, and personal preferences to determine the best path forward. I believe that germline testing is critical for any patient presenting with de novo disease. If a patient has not yet undergone testing, they should do so immediately, because the results can significantly impact treatment strategy.

For instance, the AMPLITUDE data² looking at niraparib [Zejula] and abiraterone acetate [Zytiga] in the hormone sensitive setting show the importance of this approach. While I have not personally prescribed a poly(ADP-ribose) polymerase [PARP] inhibitor in this specific setting yet, it is a management option to consider, particularly for patients with a strong family history or known genetic markers. Fortunately, the turnaround time for germline genetic testing is now very efficient, making it a practical part of the initial workup.

For a patient with metachronous, low-volume disease, the prognosis is generally favorable. The NCCN guidelines categorize various therapies to help guide our selections. Apalutamide and enzalutamide are both considered category 1 options, and in my view, enzalutamide has proven to be as effective as other agents in this class. Darolutamide [Nubeqa] is also listed within the guidelines as a category 2B recommendation for consideration.

The timeline of clinical trials in this space shows how deeply these therapies have penetrated our practice. The LATITUDE study [NCT01715285]³ was among the first to demonstrate the benefit of adding abiraterone acetate to the treatment regimen. This was followed by the integration of other potent androgen receptor signaling inhibitors, including enzalutamide [Xtandi] and apalutamide [Erleada]. These trials have been ongoing for a significant amount of time, providing us with robust data to support our current management of hormone sensitive disease.

In what setting would you consider a triplet regimen?

Looking at the ARASENS trial data [NCT02799602],⁴ triplet therapy is most likely to benefit patients with high-volume disease, the HR was 0.7, and this was likewise true in PEACE-1 [NCT01957436].⁵ Conversely, for patients with low-volume disease, the benefit is less clear.

This raises several important questions. Does every patient with high-volume disease need docetaxel? Should no patient with low-volume disease receive it? And how do we interpret these data in the context of a control arm that does not reflect current standard of care in the US?

Perhaps the more fundamental question is whether anyone truly needs triplet therapy? It is possible that androgen deprivation therapy plus an androgen receptor pathway inhibitor, such as enzalutamide, is sufficient. How much additional benefit does docetaxel contribute on top of an androgen receptor pathway inhibitor [ARPI] backbone? That question remains unanswered, as no trial has directly evaluated the addition of docetaxel to an ARPI in this setting.

Is there evidence that low-volume disease benefits from doublet hormonal therapy?

A research group from the Mayo Clinic conducted a living network meta-analysis published in European Urology with Irbaz Bin Riaz, MD, PhD, as the first author.⁶ The investigators analyzed data from various clinical trials to develop a synthetic control, providing a framework for clinicians to use when counseling patients.

The analysis addresses the clinical utility of adding docetaxel to androgen deprivation therapy and evaluates the magnitude of survival benefit provided by various treatment permutations. By using a mixed effects model for overall survival, the researchers compared different treatment arms against a theoretical baseline. These data allow for a more nuanced understanding of which patients might benefit most from specific intensive regimens compared with standard approaches.

REFERENCES

1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 5.2026. Accessed April 29, 2026. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

2. Attard G, Agarwal N, Graff JN, et al. Phase 3 AMPLITUDE trial: niraparib (NIRA) and abiraterone acetate plus prednisone (AAP) for metastatic castration-sensitive prostate cancer (mCSPC) patients (pts) with alterations in homologous recombination repair (HRR) genes. J Clin Oncol. 2025;43(suppl 17):5006-5006. doi:10.1200/JCO.2025.43.17_suppl.LBA5006

3. Fizazi K, Tran N, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi:10.1056/NEJMoa1704174

4. Saad F, Hussain MHA, Tombal B, et al. Deep and durable prostate-specific antigen response to darolutamide with androgen deprivation therapy and docetaxel, and association with clinical outcomes for patients with high- or low-volume metastatic hormone-sensitive prostate cancer: analyses of the randomized phase 3 ARASENS study. Eur Urol. 2024;86(4):329-339. doi:10.1016/j.eururo.2024.03.036

5. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1

6. Riaz IB, Ahmed Naqvi SA, Faisal KS, et al. Comparative survival in metastatic hormone-sensitive prostate cancer by volume of disease and timing of metastasis: a living network meta-analysis. Eur Urol. 2026;89(1):31-44. doi:10.1016/j.eururo.2025.09.007