From the Guidelines
Starting with Docetaxel followed by Lutetium-177 (LU177) is likely to provide better overall survival (OS) for most patients with metastatic castration-resistant prostate cancer (mCRPC) compared to starting with LU177 and then having Docetaxel. The rationale for this sequence is based on the established efficacy of Docetaxel in first-line treatment, its potential to reduce tumor burden before targeted therapy, and the observation that patients may become too frail after disease progression to tolerate chemotherapy if it's delayed 1. Additionally, LU177 appears to maintain efficacy even after chemotherapy exposure, whereas some patients who receive LU177 first might develop resistance patterns that could compromise subsequent chemotherapy response.
When considering the treatment sequence, it's essential to individualize based on patient factors including age, performance status, symptom burden, extent of disease, and PSMA expression levels. For patients with high PSMA expression and limited visceral disease, starting with LU177 might be reasonable, especially if they have contraindications to chemotherapy. However, the current evidence from studies such as the CHAARTED and STAMPEDE trials supports the use of Docetaxel as an upfront option for men with castration-naïve prostate cancer and distant metastases, with a survival benefit observed in these patients 1.
In terms of treatment specifics, Docetaxel is typically administered at 75 mg/m² intravenously every 3 weeks for up to 10 cycles, while LU177-PSMA therapy is given as 4-6 cycles at 6-8 week intervals. The properties of LU177, including its physical half-life and gamma emission lines, allow for posttreatment imaging and dosimetry assessments 1.
Key considerations for treatment sequencing include:
- Patient performance status and ability to tolerate chemotherapy
- Extent of disease and presence of visceral metastases
- PSMA expression levels and potential for targeted therapy
- Presence of contraindications to chemotherapy or targeted therapy
- Individual patient preferences and values.
Ultimately, the decision on treatment sequence should be made on a case-by-case basis, taking into account the latest evidence and individual patient factors. The most recent and highest quality study, such as the one published in the Journal of the National Comprehensive Cancer Network, should guide treatment decisions 1.
From the Research
Overall Survival (OS) Comparison
- The comparison of overall survival (OS) between starting with Docetaxel and then proceeding with Lutetium-177 (LU177) versus starting with Lutetium-177 (LU177) and then having Docetaxel is a complex one, with various studies providing insights into different aspects of this comparison 2, 3, 4, 5, 6.
- A study published in The Lancet. Oncology in 2024 found that [177Lu]Lu-PSMA-617 followed by docetaxel improved antitumour activity in patients with de-novo high-volume metastatic hormone-sensitive prostate cancer compared with docetaxel alone, without increased toxic effects 2.
- Another study published in the European journal of nuclear medicine and molecular imaging in 2025 suggested that Lu-PSMA therapy provides significantly more favorable PFS and OS outcomes in taxan-naïve mCRPC patients after previous ARPI treatment, relative to ARPI or docetaxel treatment 3.
- A phase 2 randomized, controlled trial published in the Journal of nuclear medicine in 2023 found that long-term outcomes with [177Lu]Lu-PSMA-617 administered earlier in the prechemotherapy setting are comparable to those with docetaxel 4.
Sequence of Treatment
- The sequence of treatment, whether starting with Docetaxel or Lutetium-177, may impact overall survival, but the current evidence does not provide a clear consensus on which sequence is superior 2, 3, 4.
- A case report published in Nuclear medicine and molecular imaging in 2021 found that re-challenge 177Lu-PSMA therapy with low-dose docetaxel as a radiosensitizer was a promising combination in metastatic castrate-resistant prostate cancer (mCRPC) 5.
- A phase I trial published in Urologic oncology in 2020 found that the combination of 177Lu-J591 delivered as a single fractionated cycle with docetaxel/prednisone is feasible in patients with mCRPC, with a strong preliminary efficacy signal 6.
Key Findings
- The available evidence suggests that both sequences of treatment, starting with Docetaxel or Lutetium-177, can be effective in improving overall survival in patients with metastatic prostate cancer 2, 3, 4.
- However, the optimal sequence of treatment remains unclear and may depend on individual patient factors and disease characteristics 2, 3, 4.
- Further research is needed to fully understand the impact of the sequence of treatment on overall survival in patients with metastatic prostate cancer 2, 3, 4.