The treatment landscape of advanced prostate cancer is undergoing exciting evolution with the advent of multiple novel agents and regimens. In this issue of AUANews Focus, we will highlight 3 key abstracts presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, potentially impacting clinical practice in men with advanced prostate cancer.

First, abstract 5000 reported the secondary endpoints of the ANZUP 1603 phase II randomized trial: TheraP, which compared ¹⁷⁷Lu-prostate-specific membrane antigen (PSMA)-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) in the post-docetaxel setting.¹ Eligibility criteria included high PSMA expression on ⁶⁸Ga-PSMA positron emission tomography/CT (at least 1 site with SUV_max [maximum standardized uptake value] ≥20), no FDG [fluorodeoxyglucose]-positive and PSMA-negative disease sites, and prior docetaxel treatment. The ANZUP investigators previously reported that the primary endpoint favored LuPSMA over cabazitaxel, with a PSA₅₀ response rate of 66% versus 37%. Similarly, PSA progression-free survival (PFS), a secondary endpoint, was significantly improved in the LuPSMA arm (HR 0.63, 95%CI 0.45–0.88, p=0.007) after a median followup of 11.3 months.² Rates of grade ≥3 adverse events were higher in the cabazitaxel arm as compared to LuPSMA arm (49% vs 32%).

At the 2022 ASCO Annual Meeting, Dr. Michael Hofman presented the data on overall survival (OS), another secondary endpoint, after a median followup of 36 months from this trial. The median OS was similar in both arms, with 19.1 months for LuPSMA and 19.6 months for cabazitaxel (p=0.99). It is worth noting that this trial was not powered for OS. In this update, PFS continued to favor LuPSMA.¹ These results show that both LuPSMA and cabazitaxel are acceptable treatment choices post-docetaxel in patients with mCRPC and high PSMA expression. However, if both agents are available, LuPSMA may be offered first based on better activity and safety profile.

Second, abstract LBA5004 provided an update of the ANZUP 1304 trial: ENZAMET.³ This phase III trial investigated the addition of enzalutamide to androgen deprivation therapy (ADT) in patients with metastatic castration-sensitive prostate cancer (mCSPC). The study randomized 1,125 patients to either enzalutamide plus ADT or ADT plus conventional nonsteroidal anti-androgen. Notably, concurrent docetaxel was allowed and was predetermined before randomization by treating physician. The trial previously has been reported to have met its primary endpoint after showing a 33% decrease in the risk of death with enzalutamide over control after a median followup of 34 months (p=0.002).⁴ At the 2022 ASCO Annual Meeting, Dr. Ian Davis presented the long-term followup results. The hazard rate of death remained 30% lower in the enzalutamide arm as compared to the control arm after a median followup of 68 months (p <0.0001).³ In a prespecified subgroup analysis, there was no improvement in OS with enzalutamide in those 45% of patients enrolled in this trial who received concurrent docetaxel (n=503). However, the receipt of docetaxel was not randomized, and the trial was not independently powered for this subgroup analysis. Nevertheless, OS benefit remained evident across the various subgroups, including those with high- and low-volume disease, and de novo and non-de novo metastasis. In conclusion, enzalutamide continued to improve OS even after a median followup of almost 6 years. Based on these results, treatment with a novel androgen axis inhibitor remains a standard of care option for men with mCPSC.

Lastly, abstract 5072 presented a post hoc analysis of the ARCHES trial, investigating the concordance of PSA and radiographic progression in patients with mCSPC treated with ADT with or without enzalutamide.⁵ ARCHES was a large, randomized phase III trial which demonstrated that enzalutamide was associated with a longer radiographic PFS and OS when added to ADT compared to placebo plus ADT in patients with mCSPC.^6,7

Results presented by Dr. Andrew Armstrong showed that 67% and 43% of patients receiving enzalutamide plus ADT or placebo plus ADT, respectively, did not have PSA progression meeting the PCWG2 (Prostate Cancer Working Group 2) criteria at the time of radiographic progression.⁵ Similarly, 34% and 15% of patients receiving enzalutamide plus ADT or placebo plus ADT, respectively, did not experience a rise in PSA from nadir at the time of radiographic progression. These findings suggest that serial PSA measures alone might not be sufficient to monitor progression and that monitoring of these patients with serial bone and soft tissue imaging may be warranted. Key takeaways are summarized in the Table.

Conflict of Interest

The authors declare the following conflicts of interest related to this study. Umang Swami is a consultant for Astellas, Exelixis, and Seattle Genetics and received institutional research funding from Janssen, Exelixis, and Astellas/Seattle Genetics. Neeraj Agarwal (lifetime disclosure) is a consultant for Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics and received institutional research funding from Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.