Combining [¹⁷⁷Lu]Lu-PSMA-617 and enzalutamide in metastatic castration-resistant prostate cancer: promising but with caveats for now

Prostate cancer is the leading cancer diagnosis among men in the United States and ranks second in estimated cancer deaths for this year (1). There have been undeniable advances in treatment over the past few decades, which have prolonged survival and improved quality of life (2-7). However, the later stages of this disease, commonly referred to as metastatic castration-resistant prostate cancer (mCRPC), continue to be problematic. Median survival from diagnosis of mCRPC remains only slightly over two years in the US (8), and new solutions are needed.

The results from the phase III VISION trial and subsequent Food and Drug Administration (FDA) approval of lutetium-177 [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA)-617 (LuPSMA) brought new hope to the field (9). This novel radiopharmaceutical extended median overall survival (OS) by 4 months in highly treatment-refractory mCRPC, while also helping men preserve their quality of life and delay symptomatic skeletal events (10). With such striking results, there is great interest in evaluating the efficacy of LuPSMA as an earlier line treatment and also in combination with other effective anti-cancer therapies.

The ENZA-p trial was a multicenter, open-label, randomized phase II trial conducted across 15 hospitals in Australia (11). It included 162 men with mCRPC who had not previously received docetaxel or androgen receptor pathway inhibitors (ARPIs) for mCRPC, with at least two risk factors for early progression on enzalutamide. Participants were randomized to either enzalutamide plus LuPSMA or enzalutamide alone. The primary endpoint was prostate-specific antigen progression-free survival (PSA-PFS). Secondary endpoints included OS, radiographic progression-free survival (rPFS), and safety. The study used an adaptive-dosing treatment plan for LuPSMA, giving two or four doses (every 6–8 weeks) depending on the findings of an interim PSMA positron emission tomography/computed tomography (PET/CT) performed on week 12. Ultimately, 81% received all four doses of LuPSMA based on results of interim PET.

The addition of LuPSMA to enzalutamide improved the primary endpoint of PSA-PFS. The median PSA-PFS was 13.0 months in the combination group versus 7.8 months in the enzalutamide monotherapy group (hazard ratio =0.43, P<0.0001). The safety profile of the combination therapy was as expected from prior studies with the most common adverse events being fatigue (75%), nausea (47%), and dry mouth (40%).

The rationale for combining these two therapies is justified. Blocking androgen receptors increases PSMA expression in prostate cancer cells (12-14), and higher PSMA expression is prognostic of a favorable response to LuPSMA (15). Additionally, we have learned from the well-stablished synergy of external beam radiation therapy (EBRT) and androgen deprivation therapy (ADT) that blocking the action of androgens may sensitize to radiation-induced death by preventing DNA repair (16-22). In the VISION trial, the addition of an ARPI to LuPSMA trended positively for OS (9).

Despite these promising findings, there are relevant limitations to consider, and questions left answered.

PSA-PFS is a relevant intermediate endpoint but can be misleading. For instance, consider Thera-P, a trial of LuPSMA versus cabazitaxel in mCRPC also conducted by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. They report an early prolongation of PSA-PFS with LuPSMA (versus cabazitaxel) that did not translate into improved OS (23,24). The long-term benefits, OS, safety, and potential resistance mechanisms to the combination therapy in ENZA-p need further data before conclusions can be drawn. The ENZA-p trial committee has already stated their intention to publish a further analysis with more mature data on OS and other secondary endpoints.

ENZA-p reports on rPFS did not consistently employ the Prostate Cancer Working Group 3 (PCWG3) criteria (25). Thus, comparisons of rPFS findings may prove challenging, but this is not a major limitation given OS will be reported later.

Regarding the adaptive-dosing strategy that was adopted with LuPSMA in the trial, it is an innovative approach, and more data are needed to fully understand the clinical impact.

As stated before, we believe that mechanistically it makes good sense to combine these two agents. The positive PSA-centric results of this trial may suggest that targeting both androgen receptor pathways and PSMA can provide complementary benefits, which could lead to improved outcomes over sequential therapy. This is particularly relevant as resistance to enzalutamide alone is a strikingly common issue, and the addition of LuPSMA offers a mechanism to overcome this resistance. That said, OS data are needed.

Investigating the synergistic effects of combining LuPSMA with other therapeutic agents could offer new avenues for enhancing treatment efficacy while maintaining the manageable safety profile LuPSMA has developed a reputation for. ENZA-p, being the first combination trial of its kind, has begun to take steps in the right direction. We look forward to more of these types of combination studies in the near future.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-172/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-172/coif). D.S.C. reports honoraria from Targeted Oncology, IntrinsiQ, MJH Life Sciences, International Centers for Precision Oncology Foundation; research funding from Janssen Biotech (Inst); support for travel from Prostate Cancer Foundation; and plays consulting or advisory roles in Janssen Biotech (Inst), Novartis (Inst). O.S. reports honoraria from Lantheus Medical Imaging, research funding from Advanced Accelerator Applications (Inst), Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Endocyte (Inst), InVitae (Inst), Janssen, Lantheus Medical Imaging (Inst), Merck (Inst), Point Biopharma, Progenics (Inst), Sanofi (Inst); support for travel from AstraZeneca, Bayer, Johnson & Johnson, Lantheus Medical Imaging, Progenics, Sanofi; has stock and other ownership of interests in Abbvie, Cardinal Health, Clarity Pharmaceuticals, Convergent Therapeutics, Fusion Pharmaceuticals, Lilly, Ratiopharm, Telix Pharmaceuticals, United Health Group; plays consulting or advisory roles in Advanced Accelerator Applications, Amgen, ARTbio, Astellas Pharma, AstraZeneca, Bayer, Blue Earth Diagnostics, Clarity Pharmaceuticals, Fusion Pharmaceuticals, Hengrui Therapeutics, Isotopen Technologien, Janssen, MacroGenics, Medscape, Merck, Northstar, Novartis, Noxopharm, Pfizer, Point Biopharma, Progenics, Ratio, Sanofi, Telix Pharmaceuticals, Tempus, TeneoBio, Tessa Therapeutics; has patents, royalties, and other intellectual property (Koochekpour, Sartor AO, inventors; Saposin C and receptors as targets for treatment of benign and malignant disorders). He also has US patent awarded in January 23, 2007 (patent No. 7,166,691); and also has expert testimony in Sanofi. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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