Dr. Dorff on the Exploration of Triplet Combination Therapies in mHSPC

Tanya Dorff, MD, medical oncologist, associate clinical professor, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses the exploration of triplet combination therapies in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The phase 3 ARASENS trial (NCT02799602) provided proof of concept for triplet therapy in patients with mHSPC, Dorff says. The study evaluated the efficacy and safety of darolutamide (Nubeqa) in combination with standard androgen deprivation therapy (ADT) and docetaxel vs placebo with ADT and docetaxel in patients with mHSPC. Findings showed that darolutamide plus ADT/docetaxel demonstrated a 32.5% reduction in the risk of death compared with ADT/docetaxel alone. In August 2022, the FDA approved darolutamide tablets in combination with docetaxel for adult patients with mHSPC, based on findings from ARASENS.

Although the phase 3 PEACE1 trial (NCT01957436) was not initially designed to address the question of the use of chemotherapy with an androgen receptor (AR) targeted agent, it did provide supportive evidence for triplet therapy, Dorff says. The study evaluated ADT and docetaxel, with or without abiraterone acetate (Zytiga) and prednisone, and with or without local radiotherapy, in patients with metastatic hormone-naïve prostate cancer. The combination of ADT, docetaxel, abiraterone acetate, and radiotherapy showed a statistically significant improvement in overall survival and radiographic PFS (rPFS). The median rPFS was 4.46 years for the combination, compared with 2.22 years for those not given abiraterone acetate.

Given the results of these trials, the main unanswered question remaining centers around how much benefit docetaxel adds when using AR inhibitors, Dorff notes, adding that neither the ARASENS nor PEACE1 answered that question.

Ongoing clinical trials can help address that question by exploring the addition of other agents to triplet therapies, such as lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly 177Lu-PSMA-617), PARP inhibitors, and PI3K inhibitors. These trials will help flush out the landscape and potentially provide additional triplet options for patients with mHSPC, Dorff concludes.