Improved mCRPC outcomes with LuPSMA in phase 3 trial

medwireNews: The PSMAfore trial of the radioligand lutetium-177-prostate-specific membrane antigen-617 (LuPSMA) has met its primary endpoint of a radiographic progression-free survival (rPFS) benefit in men with metastatic castration-resistant prostate cancer (mCRPC). The risk for radiographic progression was a significant 57% lower with LuPSMA than the control option of an androgen receptor pathway inhibitor (ARPI) switch, reported the presenting author at the ESMO Congress 2023 in Madrid, Spain. Oliver Sartor (Mayo Clinic, Rochester, Minnesota, USA) added that the secondary and exploratory endpoints also favored LuPSMA and the safety profile was manageable. The discussant – Christopher Sweeney, from the University of Adelaide in South Australia – congratulated the investigators on conducting a “well-powered” trial with “clear documentation of anticancer activity,” as evidenced by cancer regressions and “major” delays in progression. “The study also provides data for the first time on benefit in patients who have not had docetaxel or are not fit for docetaxel in a randomized phase 3 setting,” he said. Nevertheless, the study does have some limitations, continued Sweeney, such as the fact that “rPFS is a modest endpoint versus overall survival [OS]” and hormone therapy switch is a “weak control.” But he acknowledged that “these are the decisions that we make when we design trials for pragmatic reasons.” The trial comprised 468 mCRPC patients who had progressed on one prior second-generation ARPI, had at least one PSMA-positive metastatic lesion on positron emission tomography, and had not received taxanes except as neoadjuvant or adjuvant therapy more than 12 months before enrollment. Participants were randomly assigned to receive either LuPSMA at a dose of 7.4 GBq every 6 weeks for six cycles or undergo an ARPI switch. Sartor noted that the primary analysis of rPFS was reported in a press release some months ago and therefore, he was presenting an updated analysis, which showed a median rPFS of 12.02 months with LuPSMA and 5.59 months with ARPI switch, a significant difference equating to a hazard ratio (HR) of 0.43. Treatment with LuPSMA achieved a significantly higher rate of radiographic objective response, at 50.7% versus 14.9% with ARPI switch; the respective complete response rates were 21.1% and 2.7%. And the experimental agent also significantly reduced the risk for a symptomatic skeletal event, at an HR of 0.35 versus control. Patients in the LuPSMA arm reported a significantly longer time to worsening of health-related quality of life and pain, as assessed by the Functional Assessment of Cancer Therapy–Prostate and Brief Pain Inventory–Short Form questionnaires, respectively, than those in the control arm, with HRs of 0.59 and 0.69, respectively. There was no significant difference in OS between the treatment arms in either the intention-to-treat analysis or the prespecified crossover adjusted analysis after a median follow-up of around 13 months, although the HR of 0.80 in the latter numerically favored LuPSMA. Sartor highlighted that 84.2% of participants in the control group crossed over to receive LuPSMA after radiographic progression, “which may have confounded the intent-to-treat analysis,” and commented that he has “never seen a phase 3 trial with this degree of crossover.” Treatment-emergent adverse events (TEAEs) of grade 3–4 were observed in fewer patients in the LuPSMA than control group, at rates of 33.9% and 43.1%, respectively, while grade 5 TEAEs occurred in a comparable 1.8% and 2.2%. The rate of dose adjustments due to TEAEs was also lower among LuPSMA-treated participants than those who had an ARPI switch, at 3.5% versus 15.1%, but the rate of discontinuation was similar, at a respective 5.7% and 5.2%. medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group ESMO Congress 2023; Madrid, Spain: 20–24 October

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Improved mCRPC outcomes with LuPSMA in phase 3 trial

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