First Quadruplet Therapy Regimen Shows Promise for Men with High-Volume Metastatic APMN Prostate Cancer
CASCARA phase 2 trial demonstrates that combining platinum-based combination chemotherapy with dual hormonal treatments is feasible, safe, and shows encouraging early activity
New York, NY — Results from the CASCARA trial (NCT03934840), the first prospective study to evaluate a four-drug systemic therapy regimen in patients with high-volume metastatic androgen pathway modulation–naïve prostate cancer (APMN, formerly castration-sensitive prostate cancer [CSPC]), have been published today in Clinical Cancer Research. The multi-center phase 2 study found that combining cabazitaxel, carboplatin, abiraterone, and androgen deprivation therapy (ADT) was feasible and safe, with promising signs of durable disease control in a patient population with significant unmet need.
Despite advances in treating metastatic prostate cancer with hormonal agents and chemotherapy, approximately 20 percent of men with high-volume disease experience progression within the first year of treatment. The CASCARA trial was designed to test whether intensifying upfront therapy — by pairing a hormonal doublet (ADT plus abiraterone) with a chemotherapy doublet (cabazitaxel plus carboplatin) — could improve outcomes for these high-risk patients, and to determine whether those with homologous recombination repair (HRR) gene mutations might benefit preferentially from this strategy.
"To our knowledge, this is the first prospective study to evaluate quadruplet systemic therapy in patients with metastatic androgen pathway modulation–naïve prostate cancer," said Emmanuel S. Antonarakis, MD, Clark Endowed Professor of Medicine in the Division of Hematology, Oncology and Transplantation at the University of Minnesota and lead author of the study. "We showed that this intensified regimen was feasible with a reasonable toxicity profile, and the early signs of clinical activity are encouraging. Importantly, our biomarker analyses revealed significant biological heterogeneity within this patient population, which underscores the need to move beyond simply counting lesions on imaging and toward classifying patients based on the genomic and transcriptomic features of their tumors to better guide treatment decisions."
Key Findings
The CASCARA trial enrolled 61 patients across eight academic medical centers in the United States through the Prostate Cancer Clinical Trials Consortium (PCCTC). Patients received six cycles of cabazitaxel and carboplatin every three weeks, followed by maintenance abiraterone and prednisone, with continuous ADT throughout. Key results include:
84.6% of patients were free of PSA or radiographic progression at 12 months (the study's primary endpoint)
12-month overall survival rate was 94.8%
12-month radiographic progression-free survival (PFS) rate was 81.1%
66.7% achieved a complete PSA response (PSA ≤0.2 ng/mL)
30.7% achieved a complete objective radiographic response
Only 8.2% of patients discontinued chemotherapy due to treatment-related adverse events
The most common side effects were fatigue, nausea, and diarrhea, and the regimen was generally well-tolerated with the support of colony-stimulating factor during chemotherapy cycles to minimize bone marrow toxicity.
Biomarker Insights
The study also incorporated exploratory genomic and transcriptomic biomarkers. Contrary to the initial hypothesis, patients with homologous recombination repair (HRR) gene mutations — present in about 20% of participants — did not fare better on this platinum-containing regimen. Instead, HRR-mutated patients showed numerically fewer complete PSA responses and a trend toward inferior PFS compared to those without such mutations. The authors note, however, that without a control arm, it remains possible that HRR mutations carry a worse natural history while still possibly conferring relative benefit from platinum-based therapy — a hypothesis that warrants further investigation.
Additional genomic findings suggested that TP53 mutations were associated with worse outcomes, while SPOP mutations and TMPRSS2–ERG fusions trended toward more favorable results. Transcriptomic analysis using the VeraCyte genomic classifier found that patients with higher Decipher scores had significantly worse PFS.
Next Steps
Speaking on the future of quadruplet therapy in advanced prostate cancer, PCCTC Medical Director and CASCARA co-principal investigator Charles J. Ryan, MD of Memorial Sloan Kettering Cancer Center stated, “Despite significant progress in recent years, patients with high-volume androgen pathway modulation–sensitive (APMS) metastatic prostate cancer face significant challenges. This study is the first to integrate platinum-based chemotherapy into the initial treatment approach for such patients in an effort to maximize initial response rates. We are encouraged by these results and are exploring ways to move forward with the first four-drug regimen in advanced prostate cancer."
The authors call for a randomized evaluation of CASCARA’s quadruplet regimen compared to a standard backbone of ADT and abiraterone, with or without docetaxel, in patients with high-risk, high-volume, or genomically unfavorable metastatic APMN prostate cancer. They emphasize that future trials should incorporate prospective genomic and transcriptomic biomarker assessment to help identify which patients are most likely to benefit from intensified platinum-containing therapy.
The CASCARA trial was supported by Sanofi-Genzyme and managed by the PCCTC. Portions of these data were previously presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.
