Prostate Cancer Highlights From ASCO 2022

At the American Society of Clinical Oncology (ASCO) 2022 meeting in early June 2022, several important abstracts pertaining to prostate, bladder, and kidney cancer were presented. Several interesting abstracts within the prostate cancer sphere were presented, of which a few will be highlighted in this article.

In the sphere of metastatic hormone-sensitive prostate cancer (mHSPC), several medications including abiraterone (LATITUDE trial¹), apalutamide (TITAN trial²), and enzalutamide (ENZAMET trial³) have been approved in recent years for use in combination with androgen- deprivation therapy (ADT). Ian Davis, MD, presented updated overall survival (OS) outcomes from the ENZAMET trial.⁴ To review, the original results in 2019 demonstrated that in 1125 patients with mHSPC enrolled in the randomized clinical trial, the 36-month OS in the experimental arm showed an 8% improvement in OS (80% vs 72%) as well as a favorable hazard ratio (HR) of 0.67.

Dr. Davis briefly reviewed the existing knowledge compiled by several trials, including those referenced above. Specifically, he explained that patients with low-volume mHSPC tend to do well with testosterone-suppressive therapies alone, whereas patients with higher volumes of disease may benefit from addition of docetaxel, stronger combinations of testosterone-suppressive therapies, or even radiation therapy delivered to the primary tumor.

Dr. Davis briefly reviewed the ENZAMET trial design. He explained that patients were stratified by volume of metastatic disease, use of docetaxel, and Eastern Cooperative Oncology Group (ECOG) performance scores among other variables prior to randomization, to receive standard ADT plus placebo or ADT plus enzalutamide. He also referenced the original data presented in 2019, taking care to remark that despite the overall OS improvement for the entire cohort, subgroup analysis of patients receiving docetaxel did not demonstrate an OS benefit.

Dr. Davis noted that updated data after a longer median follow-up time of 68 months may offer further insights into the use of enzalutamide in the mHSPC population. The primary goal of the updated analysis was to study the results of enzalutamide use in patients who had nonmetastatic (M0) versus metastatic (M1) disease at diagnosis, as well as the presence of high-volume disease at trial entry.

The overall cohort analysis for OS demonstrated a sustained survival benefit (favorable HR of 0.70; P<0.001), with 10% improvement in OS at 60 months (67% vs 57%) in the experimental arm. Before presenting data on the subcohort analyses, Dr. Davis reiterated that use of docetaxel in the enrolled patients was solely at the discretion of each investigator, with 45% of the population ultimately planned to undergo concurrent docetaxel therapy.

Presentation of the OS analysis stratified by subgroups demonstrated some interesting findings. Dr. Davis explained that the effect of enzalutamide was most prominent in patients with low-volume disease (HR, 0.54 vs 0.79l; P=0.06) and those with no docetaxel exposure (HR, 0.60 vs 0.82; P=0.09). Overall, the updated results demonstrated that no statistically significant differences were found between subgroups with use of enzalutamide; however, use of enzalutamide appears particularly useful in patients with low-volume mHSPC. In concluding remarks, Dr. Davis further noted that addition of enzalutamide in patients with mHSPC receiving ADT shows a clinically significant improvement in OS.

Several developments related to prostate-specific membrane antigen (PSMA) were also presented at ASCO 2022, including updated results from the TheraP phase II trial (NCT03392428)⁵ exploring the utility of lutetium-177 (¹⁷⁷Lu)-PSMA-617 compared with cabazitaxel therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

The TheraP trial enrolled 200 patients (291 originally screened) with mCRPC demonstrable on positron emission tomography (PET) imaging, with 99 patients randomized to ¹⁷⁷Lu-PSMA-617 and 101 randomized to cabazitaxel therapy. The original results published in 2021,⁶ demonstrated that patients randomized to ¹⁷⁷Lu-PSMA-617 had a higher rate of PSA response compared with the cabazitaxel arm (66% vs 37%) as well as having a lower rate of significant (grade 3/4) adverse events (AEs; 33% vs 53%).

Michael S. Hoffman, MBBS, lead author for the original publication from the Peter MacCallum Cancer Centre in Melbourne, Australia, reported on longer-term follow-up outcomes for this trial. PSA progression free survival (PFS) in the ¹⁷⁷Lu-PSMA-617 arm was improved compared with the cabazitaxel arm (HR, 0.63; P=0.007), with a 2.1-month improvement (7.1 vs 5 months). Despite these promising results, no significant difference in OS was noted between the 2 arms. Updated data on AEs were also presented and demonstrated a consistent rate of lower grade 3/4 AEs with ¹⁷⁷Lu-PSMA-617 compared with cabazitaxel (32% vs 49%).

The updated data from the TheraP trial demonstrate that due to improvements in PFS and an improved safety profile, ¹⁷⁷Lu-PSMA-617, despite having no demonstrable OS benefit compared with cabazitaxel, can still serve as a therapy of choice in mCRPC that is refractory to treatment (docetaxel, androgen pathway inhibition). Furthermore, the favorable administration schedule (6 weeks vs 3 weeks for cabazitaxel) may provide an already frail patient population further flexibility.

Another important abstract related to ¹⁷⁷Lu-PSMA-617 was presented by Andrew Armstrong, MD, MSc, of Duke University, on behalf of author Philip Kuo, MD, exploring the utility of gallium-68 (⁶⁸Ga)-PSMA-11 PET imaging for prognostic ability in patients receiving ¹⁷⁷Lu-PSMA-617 therapy for mCRPC.⁷ Dr. Armstrong briefly reviewed the results of the VISION trial,⁸ originally published in 2021, demonstrating statistically significant improvements in radiographic PFS (rPFS; HR, 0.40; 8.7 vs 3.4 months) and OS (HR, 0.72; 15.3 vs 11.3 months) in the ¹⁷⁷Lu-PSMA-617 arm of patients with refractory mCRPC. The purpose of this VISION trial subanalysis was to elucidate associations between pretreatment PET/computed tomography (CT; ⁶⁸Ga-PSMA-11) imaging and clinical outcomes from ¹⁷⁷Lu-PSMA-617 therapy (ie, rPFS and OS).

The subcohort analysis included 548 of 551 patients for evaluation of OS and 382 patients for evaluation of rPFS and PSA response. Dr. Armstrong explained that the mean standard uptake volume (SUV_mean; ie, mean counts of detectable lesions across the entire body) was found to be a significant predictor of important treatment indicators, such as rPFS, OS, and PSA response. In regard to rPFS, Dr. Armstrong explained that patients with the highest SUV_mean values tended to receive the greatest rPFS benefit from ¹⁷⁷Lu-PSMA-617 therapy, with values >10.2 having a median rPFS of 14.1 months. This is in comparison to SUV_max (region with highest detectable counts), which was found to not be a significant predictor of any endpoints. Finally, in regard to OS, SUV_mean was again demonstrated to be a statistically significant predictor (HR, 0.92; P<0.001).

In concluding remarks, Dr. Armstrong explained that this analysis of the VISION trial data supports the idea that patients with treatment-refractory mCRPC should undergo ⁶⁸Ga-PSMA-11 PET/CT to help identify which individuals would benefit most from PSMA-directed radioligand therapy such as ¹⁷⁷Lu-PSMA-617. Information such as SUV_mean values garnered from these scans can help clinicians predict radioligand treatment outcomes.

References

1. Fizazi K, Tran N, Fein L, et al; for the LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352-360. doi: 10.1056/NEJMoa1704174
2. Chi KN, Agarwal N, Bjartell A, et al; for the TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307
3. Davis ID, Martin AJ, Stockler MR, et al; for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi: 10.1056/NEJMoa1903835
4. Davis ID, Martin AJ, Zielinski RR, et al; for the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP). Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;14(17 suppl):abstract LBA5004. doi: https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.17_suppl.LBA5004
5. Hofman MS, Emmett L, Sandhu SK, et al. TheraP: A randomised phase II trial of 177Lu-PSMA-617 (LuPSMA) theranostic versus cabazitaxel in metastatic castration resistant prostate cancer (mCRPC) progressing after docetaxel: initial results (ANZUP protocol 1603). J Clin Oncol. 2020;38(15 suppl):abstract 5500. doi: 10.1200/JCO.2020.38.15_ suppl.5500
6. Hofman MS, Emmett L, Sandhu S, et al; for TheraP Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. doi: 10.1016/S0140-6736(21)00237-3
7. Kuo P, Hesterman J, Rahbar K, et al. [68Ga] Ga-PSMA-11 PET baseline imaging as a prognostic tool for clinical outcomes to [177Lu] Lu-PSMA-617 in patients with mCRPC: a VISION substudy. J Clin Oncol. 2022;40(16 suppl):abstract 5002. doi: 10.1200/ JCO.2022.40.16_suppl.5002
8. Morris MJ, De Bono JS, Chi KN, et al; on behalf of the VISION Trial Investigators. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(15 suppl):abstract LBA4. doi: 10.1200/ JCO.2021.39.15_suppl.LBA4