Oliver Sartor MD
Written by
Oliver Sartor MD
Introduction
The landscape of advanced prostate cancer treatment saw significant developments in 2024, with three phase III trials potentially reshaping clinical practice. These studies — ARANOTE, PEACE-3, and PSMAfore — each addressed distinct patient populations and treatment strategies, offering new insights into optimal therapeutic approaches.
ARANOTE: Expanding treatment options in metastatic hormone-sensitive disease
The ARANOTE trial demonstrated the efficacy of darolutamide in metastatic castrate-sensitive prostate cancer (mCSPC) through a straightforward study design.1 The trial randomized 669 patients to receive either androgen deprivation therapy (ADT) plus placebo or ADT plus darolutamide. The results, published in the Journal of Clinical Oncology, revealed that the addition of darolutamide to ADT significantly improved radiographic progression–free survival (rPFS), with a hazard ratio of 0.54 (95% CI, 0.41–0.71). The median rPFS was not reached in the darolutamide arm versus 25 months in the placebo arm. Overall survival (OS) outcomes showed a favorable trend, with a hazard ratio of 0.81 (95% CI, 0.59–1.12); however, the data are immature. Notably, darolutamide demonstrated superior tolerability, with fewer treatment discontinuations in the darolutamide arm (6.1%) than in the placebo arm (9.0%). These findings are particularly significant as they support darolutamide use beyond its current FDA-approved indication with ADT plus docetaxel.
Although the trial is clearly positive, the use of ADT monotherapy in the control arm raised many eyebrows when reported. The trial was conducted predominantly in countries where androgen receptor pathway inhibitors (ARPIs) were not available. Regardless, running a trial with ADT monotherapy in today's world would not be considered appropriate in most of the major prostate centers.
PEACE-3: Optimizing treatment in bone-metastatic castrate-resistant prostate cancer
PEACE-3 investigated the combination of enzalutamide and radium-223 versus enzalutamide alone in bone-metastatic castrate-resistant prostate cancer (mCRPC), focusing on patients with asymptomatic or mildly symptomatic disease.2 The study population had limited prior exposure to newer therapies, with approximately 30% having received docetaxel in the hormone-sensitive setting and only 2% to 3% having prior abiraterone exposure. The trial (N = 446) demonstrated improved rPFS, with a hazard ratio of 0.69 (95% CI, 0.54–0.87), representing a median improvement of 3 months (median rPFS, 16.4 months with enzalutamide vs 19.4 months with combination therapy). The OS analysis, conducted after 80% of anticipated events, showed a hazard ratio of 0.69 (95% CI, 0.52–0.90), with a median OS of 35.0 months in the control arm and 42.3 months in the radium-223 plus enzalutamide arm. The combination therapy was well-tolerated.
A crucial protocol amendment emerged during the trial when the data monitoring committee observed unacceptably high fracture rates. This led to the mandatory use of bone health agents such as zoledronic acid or denosumab, which dramatically reduced the fracture risk. It is absolutely clear that enzalutamide and radium-223 together should not be used without concomitant bone health agents such as zoledronic acid or denosumab. The trial's complete findings await peer-reviewed publication.
There are several caveats when analyzing the PEACE-3 data. First of all, the majority of patients had never received a prior ARPI — ADT monotherapy was the only typical prior therapy. In today's world, ADT monotherapy is not considered to be the standard of care; thus, current treatment practices in major centers may not encounter this particular patient population except on rare occasions. It was also notable that the statistics for OS violated the assumptions for proportional hazards. Thus, there is some statistical controversy regarding the OS results.
PSMAfore: Advancing PSMA-targeted therapy
PSMAfore evaluated 177Lu-PSMA-617 against ARPI switch in patients with PSMA PET–positive mCRPC who had progressed after initial ARPI therapy.3 The study specifically excluded patients with prior docetaxel treatment except in the adjuvant setting. Among the 468 randomized patients, the most mature analysis of rPFS showed a hazard ratio of 0.49 (95% CI, 0.39–0.61), favoring the isotopic arm (median rPFS, 11.60 months with lutetium and 5.59 months with ARPI switch). The trial permitted crossover for patients in the control arm upon centrally confirmed radiographic progression, provided they met the eligibility criteria for lutetium treatment. With a 57% crossover rate in the intent-to-treat population, the OS analysis showed a hazard ratio of 0.98 (95% CI, 0.75–1.28). Secondary endpoints, including objective response rate and health-related quality of life, consistently favored the lutetium arm. The isotope was well-tolerated.
The obvious caveat when considering these results is that the OS benefit shows no positive impact of lutetium treatment. Although the crossover rate is high, it is not completely clear that the lack of OS benefit is due to the crossover. It is also clear that ARPI change may not be the best control group. Many of these patients in the real world might have received docetaxel. The FDA and other regulatory agencies will carefully analyze these data before issuing an opinion.
Clinical impact and future directions
These trials collectively suggest several practice-changing implications. First, the ARANOTE results support the broader application of darolutamide in mCSPC, particularly benefiting docetaxel-ineligible/docetaxel-adverse patients. Second, PEACE-3 establishes a role for combination therapy with enzalutamide and radium-223 while emphasizing the mandatory requirement for bone health agent support. Third, PSMAfore suggests potential earlier integration of 177Lu-PSMA-617 in the mCRPC treatment sequence; however, the neutral OS findings — potentially influenced by crossover — warrant careful consideration in treatment sequencing decisions.
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Cancer Management Prostate Prostate Cancer
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Additional Info
References
Disclosures
Saad F, Vjaters E, Shore N, et al. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol. 2024 Sep 16. Doi: 10.1200/JCO-24-01798. Online ahead of print.
Gillessen S, Choudhury A, Saad F, et al. LBA1 A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Ann Oncol. 2024;35(2_suppl):S1254.
Morris MJ, Castellano D, Herrmann K, et al. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404(10459):1227-1239.
Published in Oncology
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