When a man with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) walks into the clinic today, the default is no longer androgen-deprivation therapy (ADT) alone but ADT plus an androgen-receptor pathway inhibitor (ARPI), with debate now centered on who needs a doublet, a triplet, or a biomarker-selected regimen, said Mark N. Stein, MD, of Columbia University Medical Center, during a recent OncLive® Scientific Interchange and Workshop.¹
During the workshop, Stein and a panel of academic and community oncologists worked through the disease continuum from diagnosis to castration resistance, weighing how volume, prostate-specific antigen (PSA) kinetics, cost, and biomarkers should guide intensification.
Top Takeaways From an OncLive Workshop on Advanced Prostate Cancer
- In CHAARTED, adding docetaxel to ADT nearly halved the risk of death in patients with high-volume mHSPC (HR, 0.63), with no clear benefit in low-volume disease
- All 4 approved ADT-ARPI doublets improved OS by approximately 30% to 40% vs ADT alone, and a deep PSA response (≤ 0.2 ng/mL) tracked with better outcomes across trials
- Adding an ARPI to an ADT-docetaxel doublet in PEACE-1 and ARASENS cut mortality risk by 25% to 32% vs the doublet alone, at the cost of added myelosuppression
How should volume, risk, and PSA kinetics guide ARPI selection in mHSPC?
Panelists opened the session by noting that with risk stratification by high-volume disease and high-risk disease still anchor first-line decisions.² Findings from the phase 3 CHAARTED trial (NCT00309985) demonstrated that docetaxel added to ADT benefited those with synchronous (HR, 0.63; 95% CI, 0.49-0.81; P < .001) and metasynchronous (HR, 0.72; 95% CI, 0.36-1.46; P = .37) high-volume disease in terms of overall survival (OS) compared with ADT alone, however the same benefit was not observed in patients with low-volume disease.3 This pattern was reproduced in the 2023 STOPCaP meta-analysis.³,⁴
Every ADT-ARPI doublet discussed improved OS over ADT alone by approximately 30% to 40%, and PSA depth was a recurring theme: Reaching a PSA of 0.2 ng/mL or lower by 6 to 7 months predicted better rPFS and OS in multiple trials.⁵⁻⁸ Choosing among them, panelists agreed, comes down less to head-to-head efficacy, which does not exist, and more to safety, interactions, and cost. "It ultimately comes down to, obviously, efficacy, but also safety and the patient that's in front of you. I don't think there's a one-size-fits-all for any particular drug," said Alexander Z. Wei, MD. Daniel Danila, MD, raised a less-discussed factor: "Medicare now caps all out-of-pocket medications to $2100 per year, both generic and brand.... I think it's a well-kept secret." Comorbidities, pill burden, and interaction profiles (darolutamide was flagged as cleanest) also shape the choice.
When does adding docetaxel or a PARP inhibitor change the calculus in mHSPC?
For higher-risk patients, the panel turned to triplet therapy. In the phase 3 PEACE-1 trial (NCT01957436), abiraterone acetate (Zytiga) added to ADT-docetaxel improved OS (HR, 0.75; 95% CI, 0.59-0.95) and progression-free survival (HR, 0.50; 95% CI, 0.34-0.71).⁹ Moreover, in the phase 3 ARASENS trial (NCT02799602), darolutamide added to ADT-docetaxel showed a similar OS benefit (HR, 0.68; 95% CI, 0.57-0.80).¹⁰ The trade-off is myelosuppression; roughly a fifth of patients discontinued treatment, mostly from docetaxel toxicity, and most panelists reserve growth factor support for dose-limiting neutropenia only.
The recently reported phase 3 ARASAFE trial (NCT05676203) of docetaxel with darolutamide/ADT found fewer grade 3 to 5 adverse effects (AEs) and less grade 3/4 neutropenia with the split-dose schedule, with comparable 1-year PSA responses.¹¹
Biomarker-selected triplets drew the liveliest discussion. In the phase 3 AMPLITUDE trial (NCT04497844), niraparib (Zejula) added to abiraterone-ADT in HRR-altered mHSPC improved radiographic progression-free survival (rPFS; HR, 0.63; 95% CI, 0.49-0.80; P = .0001), more so with BRCA mutations (HR, 0.52; 95% CI, 0.37-0.72; P <.0001), though OS remains immature and grade 3 or higher AEs were more frequent.¹² Panelists welcomed the option but flagged implementation gaps: germline vs somatic testing, timing sequencing before treatment starts, and a placebo-arm crossover to PARP inhibitors that muddies the OS signal. "I feel like it's like a video, like a toy that came without a user manual, like a computer that came without instructions," Stein said of applying the regimen. Wei was more skeptical of broad testing mandates: "We're doing all of this work to find perhaps like the small group of patients who may benefit...; it just seems sometimes like a misuse of resources."
