Dr Smith on the Use of Doublet vs Triplet Therapies in mHSPC

"The most important thing we can do as a community is to practice evidence-based medicine and at least provide doublet therapy [with] ADT plus an ARPI to the vast majority of patients with mHSPC."

Matthew R. Smith, MD, PhD, the Claire and John Bertucci Endowed Chair in Genitourinary Cancers at Massachusetts General Hospital, as well as a professor of medicine and the director of the Genitourinary Malignancies Program at Harvard Medical School, discussed patient characteristics and disease factors that influence his decision to use doublet or triplet therapy regimens in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Smith noted that although a strong body of high-level evidence supports treatment intensification in this population, the application of that evidence in routine practice has lagged. Consequently, many patients in the United States still receive androgen deprivation therapy (ADT) alone as the initial systemic therapy for metastatic disease.

Furthermore, Smith emphasized that practicing evidence-based medicine requires providing doublet therapy, consisting of ADT plus an androgen receptor pathway inhibitor (ARPI), to most patients with mHSPC. Smith added that ADT alone may only be appropriate for a small minority of patients, such as older, frail patients or those with mild disease who may not be suitable candidates for intensification. Overall, however, ADT plus an ARPI is now the standard of care for patients with mHSPC, according to Smith.

The secondary question is determining which patients should also receive chemotherapy plus docetaxel in addition to the ADT/ARPI doublet, Smith continued. He asserted that this question will likely never be completely answered in a prospective randomized controlled trial. Therefore, oncologists are left interpreting data from ADT/docetaxel doublet studies, as well as from triplet studies. Smith referred to studies such as the phase 3 ARASENS trial (NCT02799602), which investigated ADT plus darolutamide with docetaxel, and the comparable phase 3 PEACE-1 study (NCT01957436), which evaluated ADT plus abiraterone (Zytiga) with or without docetaxel. Smith clarified that these triplet studies did not address the role of docetaxel in this population but instead addressed the role of the ARPI. An evidence gap accordingly remains, he stated.

Because of this gap in evidence, Smith explained that he and many colleagues across the country reserve triplet therapy primarily for the youngest, healthiest patients. These patients are considered the least likely to be harmed by the addition of docetaxel and the most likely to benefit from this agent due to the severity of their disease, such as if they have de novo, high-burden metastatic disease, he noted. Smith concluded that although other potential predictors of poor outcomes—including loss of tumor suppressor genes, tumor genetic testing, or high Decipher scores—are being investigated, they have not yet been validated as predictive biomarkers for the benefit of treatment intensification in mHSPC.