The current standard of patients with de novo metastatic hormone sensitive prostate cancer (mHSPC) is to offer androgen deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPI). In addition, upfront 6 cycles of docetaxel, if patient is eligible, and prostate radiotherapy for those with low-volume disease are recommended. BRCA mutations (BRCAm) and neuroendocrine differentiation (NED) confer a poor prognosis in mHSPC and the current standard of care for these patients remains suboptimal. While PARP inhibitors have shown efficacy in BRCAm castration-resistant prostate cancer, concerns exist about their toxicity and resistance when used earlier in the mHSPC setting. Carboplatin has demonstrated activity in BRCAm and neuroendocrine tumors but has not been extensively studied in mHSPC. The combination of carboplatin and docetaxel is expected to enhance treatment efficacy and delay progression.
Histologically or cytologically proven adenocarcinoma of the prostate (any T stage, Gleason score or PSA level).
De novo metastatic disease documented by a positive bone scan or CT scan or an MRI. For patients with nodal metastases only, only patients with extra-pelvic enlarged lymph nodes (lymph nodes located above the iliac bifurcation) can be included if they have either: at least one extra-pelvic lymph node ≥ 2 cm, or extra-pelvic lymph node(s)≥1 cm if the patients also have at least one pelvic lymph node ≥ 1.5 cm.
Presence of pathogenic BRCA gene alteration (BRCAm cohort) OR histologically adenocarcinoma of the prostate with neuroendocrine differentiation (NED cohort)
Circulating tumor DNA (ctDNA) analysis
Patients with previous definitive local treatment directed to prostate primary cancer (radiotherapy, brachytherapy, radical prostatectomy, ultrasound, cryotherapy, or other). A previous trans-urethral resection of the prostate (TURP) and previous local treatments of metastases are allowed.
Prior cytotoxic chemotherapy or biological therapy for the treatment of prostate cancer. Prior exposure to carboplatin or other platinum containing compounds.
Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropath\>= grade 2, per the Common Terminology Criteria for Adverse Events version 6.0.
Patients known to be human immunodeficiency virus (HIV) positive, symptomatic viral hepatitis or chronic liver disease.
Parallel
Experimental
DrugLifelong continuous ADT and darolutamide, similarly to standard of care, with the addition of docetaxel (60mg/m² per cycle) and carboplatin, with an area under the curve (AUC) of 4 mg/mL/min (AUC 4), 6 cycles + G-CSF support. For eligible patients, prostate radiotherapy, at least 3 weeks after the completion of chemotherapy.
Radiographic progression-free survival
To demonstrate that the addition of carboplatin to SoC therapies prolongs radiographic progression-free survival in patients with de novo mHSPC harboring a BRCA gene alteration and in patients with de novo mHSCPC showing neuroendocrine differentiation. Radiographic progression is defined according to the Prostate Cancer Working Group 4 (PCWG4) criteria.
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Gustave Roussy, Cancer Campus, Grand Paris
Lead sponsor
PHRC, Ministry of Health France
Collaborator
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