Triplet Not Always Better Than Doublet in mCSPC

For men with metastatic castration-sensitive prostate cancer (mCSPC), a combination of three drugs may not always be better than two drugs, say researchers.

Contemporary androgen deprivation therapy (ADT) combined with either docetaxel or an androgen pathway inhibitor (API) — known as doublet therapy — has been shown to improve both progression-free survival and overall survival in the first-line treatment of men with mCSPC.

However, two recently published clinical trials, PEACE-1 and ARASENS, showed that triplet therapy with an API plus ADT and docetaxel further improved survival compared with an API plus docetaxel doublet in heterogenous study populations.

So does that mean that triplet therapy is the new standard for first-line systemic therapy for men with mCSPC?

Not necessarily, say authors of a new systematic review and meta-analysis.

They present evidence suggesting that men with de novo high-volume disease may benefit most from triplet therapy, whereas men with recurrent low-volume disease may fare better with API-based doublet therapy.

“The findings of this systematic review and meta-analysis indicate that the decision of treatment intensification with triplet therapy for patients with mCSPC must be considered carefully by accounting for the volume of disease, the timing of metastatic presentation, and API doublet options with significant survival benefit and fitness for chemotherapy,” write Irbaz Bin Riaz, MD, PhD, from the Dana-Farber Cancer Institute in Boston, and colleagues at multiple US centers.

Results of their “living” systematic review and meta-analysis, so-called because it used weekly updates to ensure that it contained the most up-to-date evidence possible, was published online on March 2 in JAMA Oncology.

In an accompanying editorial, Deaglan J. McHugh, MD and Howard I. Scher, MD, from Memorial Sloan Kettering Cancer Center in New York, emphasize the importance of choosing therapy based on disease status and individual patient characteristics.

“As always, a personalized, risk-adapted strategy remains central to shared decision-making, with clear counseling on the risk-benefit ratio of the available treatment options. Crucial going forward is to be able to deconvolute the heterogeneity of hormone-sensitive metastatic disease to better tailor the class, choice, and sequencing of therapy to optimize the outcome for the individual in need of treatment,” they write.

McHugh and Scher also caution, however, that evolution in academic, evidence-based practice may be slow to disseminate into the real world.

“Recent reports indicate that a relative majority of patients in a community oncology setting still receive ADT monotherapy or ADT with a first-generation anti-androgen in the front-line m[C]SPC setting, including patients with visceral involvement. This variation in use could broaden with the advent of docetaxel-containing triplet regimens,” they write.

Living Meta-Analysis

For their study, Riaz and colleagues searched the MEDLINE and Embase databases for phase 3 randomized trials evaluating first-line treatment options for mCSPC through June 2021, with weekly automated searches thereafter to keep the data as current as possible through July 10, 2022, when the analysis was performed.

They identified a total of 10 randomized controlled trials involving 11,043 patients, including patients treated with triplet combinations of either abiraterone acetate (Zytiga) or darolutamide (Nubeqa) plus docetaxel and ADT, or doublets of apalutamide (Erleada), enzalutamide (Xtandi), or abiraterone plus ADT; docetaxel plus ADT; orteronel (TAK-700) plus ADT; or a nonsteroidal anti-androgen plus ADT.

They found that based on current evidence among the overall patient population, the triplet combinations containing darolutamide or abiraterone afforded superior overall survival compared with docetaxel plus ADT, with respective hazard ratios (HRs) of 0.68 and 0.75.

However, in the overall population, the triplets did not perform significantly better against docetaxel plus ADT compared with API doublets.

In the subgroup of patients with high-volume disease, abiraterone plus docetaxel and ADT improved overall survival compared with docetaxel plus ADT (HR, 0.72), but not compared with either abiraterone, enzalutamide, or apalutamide plus ADT.

Among patients with low-volume disease, the triplet containing abiraterone did not appear to improve overall survival compared with doublets containing any of the APIs plus ADT, or with docetaxel plus ADT.

“Our analysis also suggests that the timing of metastatic presentation may be particularly important for patients with low-volume disease. Patients with low-volume metachronous (recurrent) presentation are less likely to benefit from D [docetaxel] doublets,” Riaz and colleagues write.

They also note that although a pooled analysis of data from the CHAARTED and GETUG-AFU15 trials showed a lack of benefit for adding docetaxel to ADT in patients with low-volume disease, that finding may have been due to metachronous (recurrent) metastases in about 25% of those patients.

In addition, the authors note that older and less fit patients with low-volume disease would be likely to have lower toxicity with API plus ADT doublets, although the choice of an API doublet “may be guided by unique toxic effects and patient-level consideration.”

The authors did not report a funding source for the study. Multiple authors reported financial relationships with pharmaceutical companies. Scher disclosed personal fees and research grants from various companies.

JAMA Oncology. Published online March 2, 2023. Article; Editorial

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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