2024 ESMO West: Metastatic Prostate Cancer Updates with Dr Lattanzi
Presenter:
Mike Lattanzi, MD, Texas Oncology
Conference:
2024 ESMO West
At the 2024 ESMO West Conference, Dr Mike Lattanzi from Texas Oncology presented findings from two key studies reported at the 2024 European Society for Medical Oncology (ESMO) Conference. The studies provided insights into the management of both hormone sensitive and castration resistant metastatic prostate cancer. Specifically, the ARANOTE trial evaluated the use of darolutamide combined with androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC), while the PEACE-3 trial assessed the efficacy of adding radium-223 to enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). Both studies highlight the advancements in treatment for improving survival and treatment outcomes in these two patient populations.
ARANOTE: Darolutamide Plus ADT in mHSPC
The ARANOTE trial explored the efficacy of combining darolutamide, an androgen receptor pathway inhibitor (ARPI), with standard ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC). This randomized, phase III trial was designed based upon the success of earlier trials such as TITAN and ARCHES, which demonstrated the superiority of doublet therapies (ADT with an ARPI) over ADT monotherapy in mHSPC.
Study Design and Population
ARANOTE enrolled patients with newly diagnosed mHSPC, randomized 2:1 to receive either darolutamide plus ADT or ADT alone. Stratification factors included the presence of visceral metastases and prior local therapy. Approximately 70% of participants had high-volume disease, and three-quarters presented with de novo metastatic disease.
Results
The primary endpoint, radiographic progression-free survival (rPFS), showed clear superiority of the darolutamide combination over ADT monotherapy. At the 24-month mark, rPFS was 70% in the combination arm, as compared to 52% with ADT alone, with a hazard ratio (HR) of 0.54. The combination showed superior efficacy across all subgroups, including those with low-volume disease.
Secondary endpoints, including time to PSA progression, and time to development of castration resistant disease, further underscored the advantages of adding darolutamide. Notably, 63% of patients in the combination arm achieved a PSA level below 0.2 ng/mL, as compared to 19% in the ADT monotherapy group. The results are clinically significant because achieving an undetectable PSA level has been shown to be a predictor of long-term survival.
Safety and Tolerability
The addition of darolutamide was overall well-tolerated, with no unexpected safety signals. Grade 3–4 adverse events were infrequent, and quality-of-life measures favored the combination therapy by virtue of delaying disease progression.
Conclusion
Results from the ARANOTE trial reinforce the role of combination therapy in mHSPC. While overall survival (OS) data will require a longer follow up, the trial confirms that darolutamide plus ADT is an effective and well-tolerated treatment option, further solidifying the shift away from ADT monotherapy. As Dr. Lattanzi noted, “Doublet therapy is now the clear standard of care for patients with mHSPC.”
“Doublet therapy is now the clear standard of care for patients with mHSPC, and ARANOTE adds darolutamide as a highly effective, well-tolerated option in this setting.”
PEACE-3: Enzalutamide with Radium-223 in mCRPC
The PEACE-3 trial evaluated the addition of radium-223, a radiologic treatment targeting bone metastases, to enzalutamide in patients with mCRPC with predominantly bone metastatic disease. Radium-223, which was previously approved based on its demonstrated survival benefits in mCRPC, was assessed in this study for its ability to synergize with enzalutamide in delaying disease progression and skeletal events for patients with mCRPC.
Study Design and Population
This European-based phase III trial enrolled patients with mCRPC who had not received prior enzalutamide or radium-223 treatment. Patients were randomized 1:1 to enzalutamide monotherapy or enzalutamide plus radium-223. Most patients had progressed from ADT monotherapy, and a minority had prior docetaxel exposure in the mHSPC setting. The trial did not initially mandate the use of bone-modifying agents (e.g., zoledronic acid or denosumab), though this was later incorporated due to concerns about fracture risk.
Results
The addition of Radium-223 significantly improved the primary endpoint of rPFS, with a hazard ratio (HR) of 0.69. At 24 months, 45% of patients in the combination arm remained progression-free, as compared to 36% in the enzalutamide monotherapy arm. This benefit was observed across subgroups, including patients with high bone lesion burden. Overall survival results showed a positive trend with the combination therapy (hazard ratio: 0.69), although the results were not statistically significant due to early crossover in the control arm. Importantly, radium-223 delayed the time to the next anticancer therapy and reduced alkaline phosphatase levels, a biomarker of bone turnover associated with radium-223 efficacy.
Safety and Fracture Risk
Radium-223 was overall well-tolerated, with low rates of grade 3–4 adverse events. Early in the trial, however, an increased fracture incidence was observed in patients not receiving bone-modifying agents. Following the protocol amendment mandating these agents, fracture rates decreased significantly. This underscores the importance of bone health management in patients receiving radium-223 therapy.
Conclusion
Results from PEACE-3 demonstrate that radium-223 enhances the efficacy of enzalutamide in bone-predominant mCRPC, offering a valuable option for these patients. The lack of mandatory bone protection at the study's outset, however, complicates the interpretation of fracture data, and Dr Lattanzi highlighted the need for further studies to refine patient selection and optimal sequencing strategies, particularly in the context of modern combination therapies for mCRPC.
“Radium-223 enhances disease control when combined with enzalutamide in bone-predominant mCRPC, but managing bone health with protective agents is critical to optimizing outcomes.”
Summary
Both ARANOTE and PEACE-3 reflect the evolving landscape of prostate cancer treatment, emphasizing the benefits of tailored combination approaches. ARANOTE confirms the value of androgen receptor inhibitors like darolutamide in mHSPC, while PEACE-3 highlights the synergistic potential of radium-223 and enzalutamide in mCRPC with bone metastases.
As Dr. Lattanzi concluded, these studies not only validate existing treatment paradigms, but also pave the way for future research. Key questions remain about the sequencing and integration of therapies, particularly as novel agents and combination strategies continue to emerge. For clinicians, the findings underscore the importance of individualized treatment plans that leverage the full spectrum of available therapies to optimize outcomes for patients with advanced prostate cancer.
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Speaker Disclosure Information: Dr Lattanzi reported the following disclosures for this presentation: Consultant and Speaker: Astellas.