Integration of doublet and triplet therapy in metastatic prostate cancer

A Urology Times Clinical Forum moderated by Marijo Bilusic, MD, PhD, convened multidisciplinary clinicians to examine contemporary management strategies for metastatic hormone-sensitive prostate cancer (mHSPC) and the evolving role of treatment intensification. The discussion emphasized how advances in systemic therapy, molecular profiling, and imaging have reshaped clinical practice, with a focus on tailoring therapy based on patient fitness, disease burden, and tumor biology.

Evolution of the treatment paradigm

Participants highlighted that androgen deprivation therapy (ADT) alone is no longer considered sufficient initial management for most patients with mHSPC. Historical reliance on monotherapy has given way to combination strategies following multiple phase 3 trials demonstrating meaningful survival improvements with the addition of androgen receptor pathway inhibitors (ARPIs) and/or chemotherapy. Doublet therapy (ADT plus an ARPI) and triplet therapy (ADT, ARPI, and docetaxel) are now widely viewed as standards of care for appropriate candidates.

Clinicians described the importance of first determining whether a patient is fit for chemotherapy. Age, comorbidities, performance status, and patient preferences were all considered critical. For patients deemed suitable, triplet therapy was frequently favored, particularly in those with high-volume or visceral disease. For patients not suitable for chemotherapy, doublet therapy with ADT and an ARPI was considered an appropriate alternative.

Balanced use of ARPIs

The forum reviewed evidence supporting multiple ARPIs, including abiraterone acetate (Zytiga), enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa), in the hormone-sensitive setting. Across studies, these agents have shown consistent reductions in risk of progression and death when added to ADT. Participants emphasized that no single ARPI was viewed as universally superior; instead, selection is individualized based on tolerability, comorbidities, drug–drug interactions, and logistical considerations.

Several clinicians noted that cardiovascular risk, metabolic effects, and the need for concomitant corticosteroids with certain agents may influence choice. Others highlighted that pill burden, adherence, and formulary restrictions also shape real-world prescribing. Overall, the group underscored that multiple ARPIs are reasonable options and should be discussed with patients in the context of shared decision-making.

Role of chemotherapy and triplet therapy

Docetaxel remains a key component of upfront intensification for selected patients. Participants described docetaxel as generally manageable, particularly when administered early in the disease course to fit patients. The concept that chemotherapy may be better tolerated and more effective when disease burden is lower was repeatedly emphasized.

Triplet therapy was viewed as particularly appropriate for younger patients, those with high-volume metastatic disease, or those with aggressive clinical features. However, clinicians also stressed flexibility, noting that patients may discontinue docetaxel after several cycles if toxicity arises while continuing on ADT plus an ARPI.

Imaging and disease classification

Advances in molecular imaging, particularly prostate-specific membrane antigen (PSMA)-PET, have altered staging and response assessment. Participants discussed how PSMA-PET often identifies additional lesions not seen on conventional imaging, which complicates traditional definitions of high- vs low-volume disease derived from earlier trials.

The group cautioned against over-interpreting isolated PSMA-PET findings, especially when PSA is declining and patients are asymptomatic. In such cases, confirmatory testing, biopsy of suspicious lesions, or short-interval follow-up may be reasonable before escalating therapy. Conventional imaging continues to play a role, in part because many clinical trials still rely on these modalities for eligibility.

Local therapy in metastatic disease

There was growing support for considering treatment of the primary tumor and selected metastatic sites in patients with low-volume or oligometastatic disease. Radiation to the prostate and, in some cases, metastasis-directed therapy were discussed as potential components of a multimodal approach. Ongoing and emerging trials evaluating these strategies were referenced as likely to further refine patient selection.

Genomics and biomarker-driven care

Participants agreed that both germline and somatic testing should be incorporated into the evaluation of patients with metastatic disease. Identification of homologous recombination repair alterations and other actionable mutations may inform later-line use of targeted therapies, including PARP inhibitors.

Although genomic classifiers are more established in localized disease, clinicians described increasing interest in applying molecular insights earlier in the metastatic setting to refine risk stratification and personalize therapy intensity.

Intermittent vs continuous therapy

The concept of intermittent androgen deprivation in selected patients with deep and durable responses generated discussion. Some clinicians reported experience with treatment breaks in patients who achieved undetectable PSA following combination therapy and local treatment. However, there was consensus that continuous therapy remains standard for most patients with metastatic disease, particularly those who do not achieve profound PSA suppression.

Real-world considerations and barriers

Despite strong evidence supporting intensification, participants acknowledged persistent undertreatment in real-world practice. Common barriers included concerns about tolerability in older patients, fear of chemotherapy, and insurance or formulary restrictions. Several clinicians noted that patient education regarding the finite duration of docetaxel and the survival benefits of combination therapy can improve acceptance.

Importantly, real-world data were discussed suggesting that outcomes with certain ARPIs may approximate those seen in clinical trials, reinforcing the external validity of trial results. Nonetheless, clinicians emphasized that patients encountered in practice are often older and have more comorbidities than trial populations, necessitating individualized treatment planning.

Patient-centered decision-making

A consistent theme was the importance of shared decision-making. Rather than rigid adherence to algorithms, clinicians advocated for transparent conversations about goals of care, expected benefits, potential toxicities, and patient values. This approach was seen as essential to optimizing adherence and satisfaction while maximizing clinical outcomes.

Conclusion

The Clinical Forum underscored that management of metastatic hormone-sensitive prostate cancer has entered an era of routine treatment intensification. Multiple ARPIs, chemotherapy, and their combinations offer substantial survival benefits when added to ADT. Optimal care requires thoughtful patient selection, balanced consideration of available agents, integration of modern imaging and genomics, and ongoing reassessment over the disease course. By individualizing therapy and engaging patients in shared decision-making, clinicians can leverage these advances to meaningfully improve long-term outcomes.