Maarten van der Doelen

General discussion and future perspectives

Combining actinium-225 labeled PSMA-617 targeted alpha-radionuclide therapy with other agents With regard to combining strategies inPSMA-targetingRLT, the combinatory use of 225 Ac PSMA and 177 Lu-PSMA has been evaluated in two small cohorts of heavily pre-treated mCRPC patients, including one study with patients who had insufficient response to 177 Lu-PSMA monotherapy. (112, 113) The combination therapy seemed to be effective, with 65% of the patients having a ≥50% PSA decline. Furthermore, the combination of these radionuclides, including a lower dose of actinium-225 when compared to 225 Ac PSMAmonotherapy cohorts, was toleratedwell and resulted in acceptable salivary gland toxicity. Future studies are necessary to evaluate the side effects and effectiveness, and to explore the best candidates for this combined treatment modality. Positioning targeted alpha-radionuclide therapies within the therapeutic landscape of mCRPC Although multiple life-prolonging agents have been approved in recent years, the optimal sequence of these agents is unclear. The combinatory use of systemic agents already in mHSPC stage has further complicated the sequencing of treatments. Phase 3 trials compare treatments in strictly selected patient populations, often regardless of the type and outcome of previous treatments, which limits the transfer into daily practice. Therefore, sequencing studies are urgently needed to guide the positioning of treatments within the therapeutic landscape of mCRPC. Positioning of radium-223 Based on the ERA 223 trial outcomes, the EMA recommended restricting radium-223 use to patients who have had two previous systemic treatments for metastatic prostate cancer or those who cannot receive other treatments. In addition, because of the increased incidence of fractures and a lower expected efficacy, radium-223 therapy was advised to be withheld in patients with less than six osteoblastic bone metastases on baseline bone scintigraphy. These new recommendations led to debate among physicians on the positioning of radium-223 in daily practice. (114) There are several reasons why patients should be offered radium-223 relatively early in the mCRPC treatment paradigm when they have bone-dominant disease. (114) Increased benefit of radium-223 has been described in asymptomatic mCRPC patients when compared to symptomatic patients. (55, 115) Additionally, the performance status of mCRPC patients deteriorates over time, which leads to worse outcomes of radium-223 treatment. (51, 116) Later in the disease course, patients are more likely to develop visceral metastases, which excludes radium-223 as therapeutic option. (117)

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