Treatment intensification reshapes outcomes in mCSPC

At a recent discussion moderated by Marijo Bilusic, MD, PhD, Genitourinary Site Disease Group Lead, GU SDD Medical Oncology Lead, and professor of clinical medicine at the University of Miami Miller School of Medicine, clinicians explored evolving treatment strategies for metastatic castration-sensitive prostate cancer (mCSPC), focusing on how advances in imaging, systemic therapy, and molecular profiling are reshaping care. Participants shared their experiences applying clinical trial data to real-world decision-making, with particular attention to the integration of darolutamide (Nubeqa) and other androgen receptor pathway inhibitors (ARPIs) into daily practice.

This summary was generated by artificial intelligence and edited by humans for clarity.

Refining the foundation of mCSPC management

Bilusic opened by emphasizing that androgen deprivation therapy (ADT) alone should rarely be offered today. Nearly all patients, unless severely frail or burdened by cardiac disease, are candidates for at least doublet therapy—ADT combined with a next-generation ARPI. The distinction between low- and high-volume disease continues to guide therapy, although new imaging modalities are changing that framework.

Although traditional definitions from CHAARTED (NCT00309985) and LATITUDE (NCT01715285) rely on conventional bone scans and CT imaging, prostate-specific membrane antigen (PSMA)-PET has revealed previously unseen disease, blurring the line between low- and high-volume cases. Even so, participants agreed that visceral metastases and more than four bone lesions remain reliable markers of high-volume disease requiring treatment intensification.

Across trials—LATITUDE, STAMPEDE (NCT00268476), ENZAMET (NCT02446405), ARCHES (NCT02677896, TITAN (NCT02489318), and ARANOTE (NCT04736199)—combination therapy has consistently improved survival. For appropriately selected patients, triplet therapy (ADT + ARPI + docetaxel) remains an important option, offering the most robust benefit for high-volume, high-risk disease.

Darolutamide’s expanding role

A focal point of the discussion was the ARANOTE trial, which examined darolutamide plus ADT versus ADT alone in men with metastatic hormone-sensitive prostate cancer who had not received chemotherapy. The study demonstrated a significant progression-free survival advantage (70.3% vs 52.1%), as well as improvements in several secondary end points, including time to pain and PSA progression.

Based on these results, the FDA approved darolutamide in June 2024 as a doublet option in mCSPC, expanding its use beyond the previously approved triplet regimen. Bilusic highlighted darolutamide’s favorable tolerability profile: minimal central nervous system penetration, low fatigue rates, and only 6% of patients discontinuing due to adverse events. These data have positioned darolutamide as one of the best-tolerated ARPIs, allowing clinicians to intensify therapy without substantially compromising quality of life.

Participants shared their real-world impressions. Many favored darolutamide for patients sensitive to fatigue or cognitive adverse events, whereas others considered it ideal for those on multiple medications, given its limited drug-drug interactions. One urologist summarized, “I’ve been leaning toward darolutamide because patients feel better on it—less fatigue, fewer complaints, and it’s easier to keep them on treatment.”

Case discussion: Imaging, progression, and intensification

Bilusic presented a 62-year-old man with a Gleason 7 tumor and prostate-specific antigen (PSA) level of 57 ng/mL who had 3 bone metastases at diagnosis. Initially treated with apalutamide (Erleada) and ADT, the patient’s follow-up PSMA-PET revealed 5 bone lesions and a new liver metastasis. Although his PSA level declined to 6.3 ng/mL, the group agreed the response was inadequate—his disease now met high-volume criteria.

In this scenario, participants recommended treatment escalation to triplet therapy, emphasizing that a PSA level of 0.2 ng/mL or less at 6 months is an emerging benchmark for optimal response. Patients who fail to achieve that depth of PSA decline may have inferior long-term outcomes and should be considered for treatment intensification.

The case also illustrated the limitations of conventional imaging, as earlier CT scans had missed the liver lesion. PSMA-PET is revealing occult metastases more frequently, prompting clinicians to adapt older trial definitions of disease burden to modern diagnostic realities.

Individualizing therapy and managing toxicity

Panelists discussed the nuances of selecting and managing ARPI therapy. Although efficacy among the 4 approved agents is broadly comparable, adverse event profiles and comorbidities often drive decision-making.

Darolutamide was widely praised for tolerability, though Bilusic noted occasional joint swelling that typically resolves with brief treatment holds or dose reductions.

Abiraterone acetate (Zytiga) remains effective but requires closer monitoring for cardiac and hepatic toxicity. Bilusic cited several patients hospitalized for heart failure and emphasized the need for liver enzyme and electrolyte monitoring.

Apalutamide and enzalutamide (Xtandi) were acknowledged for efficacy but can cause fatigue and cognitive changes in some patients.

Dose individualization was a key takeaway. Many older patients maintain excellent disease control at half doses, minimizing adverse events without sacrificing response.

Cardiovascular care was another recurring theme. Bilusic noted that only approximately 40% of patients nationwide receive baseline cardiac evaluation before starting hormone therapy. He urged clinicians to obtain EKG, lipid panels, and DEXA scans at initiation and to monitor vitamin D levels, citing data linking deficiency to worse cancer outcomes.

Monitoring and sequencing strategies

The panel agreed that a rising PSA alone should not prompt therapy changes in mCSPC. Instead, treatment should continue until radiologic or symptomatic progression occurs. “If scans are stable and the patient feels well, stay the course,” Bilusic said. Early switching, he warned, can shorten the duration of effective therapy.

Participants described using stereotactic body radiotherapy (SBRT) to treat oligometastatic lesions detected on PSMA-PET, delaying systemic escalation and extending remission. Trials such as TRIPLE-SWITCH and DREAM are exploring PSA-based escalation and treatment holidays for deep responders.

Comprehensive genomic testing is now routine. All participants endorsed germline and somatic profiling at diagnosis, with findings such as BRCA1/2, ATM, PTEN, and RB1 guiding prognosis and treatment intensity.

Expanding options and real-world integration

Bilusic highlighted the growing number of therapies available after ARPI-based regimens. Lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617; Pluvicto), although not universally durable, offers meaningful benefit when used earlier in disease progression. Radium-223 (Xofigo) remains valuable for bone-predominant disease, particularly in older patients or those unfit for chemotherapy.

Sipuleucel-T (Provenge) was discussed as most effective when introduced early in castration-resistant disease, while PSA remains low. Bilusic explained that sipuleucel-T works by slowing PSA velocity, and thus requires several months to yield visible benefit.

The moderator also shared practical insights from his own practice, including use of darolutamide monotherapy for patients who decline ADT, paired with tamoxifen to mitigate gynecomastia. Select cases of testosterone “bipolar” therapy were also mentioned for slow-growing, nonvisceral disease, though applied only in highly specific situations.

Defining goals and maintaining quality of life

Across the discussion, participants agreed that the main objective in mCSPC is to prolong the hormone-sensitive state and delay transition to castration resistance. Bilusic summarized, “Our patients rarely die from hormone-sensitive disease—the goal is to keep them in that state as long as possible, while maintaining a good quality of life.”

Setting clear expectations—such as targeting a PSA level of ≤0.2 ng/mL and discussing when escalation may be warranted—helps align treatment goals with patient understanding.

The discussion closed with optimism about the rapid pace of progress in prostate cancer therapy. With the expanding use of agents like darolutamide, the integration of molecular diagnostics, and advances in targeted radiation and radioligand therapies, clinicians now have unprecedented tools to personalize care for men with mCSPC.