Key updates of ongoing trials for PCa treatments were presented at the American Society of Clinical Oncology (ASCO) 2022 Annual Meeting, including a 5-year OS update for the ENZAMET study in mHSPC, a 3-year update for the TheraP study, and exploratory subgroup analyses for the VISION study of 177Lu-PSMA-617 (Lu-PSMA) in pre-treated mCRPC. Detailed highlights from the latest reports are presented below.
ENZAMET 5-Year Update – Xtandi® plus ADT Provided a Statistically Significant Improvement in OS for Patients with mHSPC Over the Active Comparator1
Prof. Ian Davis, a medical oncologist from Monash University and Eastern Health, Melbourne, Australia, presented a 5-year OS update from ENZAMET, an ongoing phase 3 randomized trial comparing the effectiveness of Xtandi® plus ADT versus an active regimen of standard NSAA (bicalutamide, nilutamide or flutamide) plus ADT in patients with mHSPC after a median follow-up of 68 months.1,4 Planned early docetaxel was permitted, with up to 2 cycles of docetaxel before randomization. Concurrent docetaxel was planned for up to 6 cycles for 45% of participants at investigator discretion based on assessment of “chemo-fitness” or predicted benefit.1 The 5-year analysis of ENZAMET demonstrated a 30% reduction in the risk of death for patients with mHSPC treated with Xtandi® versus NSAA (Figure 1).1 Overall, 5-year survival was 67% for patients treated with Xtandi® versus 57% for the NSAA active comparator (Figure 1).1 There was substantial crossover (76% of patients) from the active comparator arm to Xtandi® or abiraterone after progression, while 26% of patients receiving Xtandi® then received abiraterone.1

Figure 1. OS outcomes in the 5-year analysis of the ENZAMET study1

Consistent OS benefits were observed in patients with both a high and low volume of disease, with or without planned early docetaxel (Figure 2).1 An OS benefit also remained apparent for patients with high-volume synchronous metastases where docetaxel was deemed necessary (HR, 0.79; 5-year OS, 55% vs 51%).1 Additionally, Xtandi® offered a PSA PFS and clinical PFS benefit when added to testosterone suppression plus docetaxel.1 Therefore, Prof. Davis suggested that the greatest benefit for triplet therapy may be in patients with the poorest prognosis (synchronous metastases; high-volume disease) who are able to receive docetaxel.1
Figure 2. Volume of disease and prior docetaxel OS subgroup analysis from ENZAMET 5-year analysis1

Xtandi® plus ADT provides substantial increases in OS that are not augmented by concurrent docetaxel
– Prof. Ian Davis1

TheraP 3-Year Update – Comparable OS Outcome and Improved PFS with Lu-PSMA Versus Cabazitaxel in Patients with mCRPC Previously Treated with Docetaxel2
Prof. Michael Hofman, a nuclear medicine physician from Peter MacCallum Cancer Centre in Melbourne, Australia, shared an update on OS in patients participating in TheraP, which is a phase 2 trial examining the activity and safety of treatment with Lu-PSMA versus cabazitaxel chemotherapy in patients with mCRPC who have received prior docetaxel treatment.2,5 This analysis was performed after a median follow-up of 3 years.2 Lu-PSMA significantly increased PSA response (66% vs 37% in the ITT population; 29% difference [95% CI, 16–42%]; p<0.0001) and improved 12-month PFS (19% vs 3%) compared with cabazitaxel in patients with mCRPC (Figure 3A).2 No difference in OS was observed (Figure 3B). Lu-PSMA also offered QoL benefits and a favourable safety profile, with patients reporting 20% fewer grade 3–4 AEs than those treated with cabazitaxel.2,6
Figure 3. PFS (A) and OS (B) updates in the 3-year analysis of the TheraP study2
Table. PSMA as a predictive biomarker for PSA response7
The use of PSMA was discussed as a predictive biomarker for PSA response. PSMA SUVmean ≥10 was found to be predictive of a higher likelihood of a favourable response with Lu-PSMA versus cabazitaxel (Table).7

“TheraP data support the choice of 177Lu-PSMA-617 over cabazitaxel for PSMA-positive progressive mCRPC patients after docetaxel and ARPi on the basis of a higher PSA response rate, greater PFS benefit and similar OS outcomes”
– Prof. Michael Hofman2

Lu-PSMA in PSMA-Positive mCRPC Patients – Prior and Concomitant Treatment Subgroup Analyses of the VISION Trial3
In the VISION study, the efficacy of Lu-PSMA in combination with protocol-permitted SoC in patients with heavily pretreated PSMA-positive mCRPC was compared with SoC alone.8 At ASCO 2022, Dr Nitin Vaishampayan, a radiation oncologist from Wayne State University School of Medicine in Detroit, MI, USA, presented a post-hoc exploratory analysis to assess the consistency of treatment effect across subgroups, based on prior and concomitant cancer-directed therapies.3
Exploratory subgroup analyses of rPFS and OS were performed by3:
aA regimen was defined as the administration of ≥2 cycles of a taxane.

Lu-PSMA offered consistent rPFS and OS benefits across all prior treatment and concomitant subgroups.3 Two hypothesis-forming signals suggesting improved OS for patients treated with Lu-PSMA were observed in patients who:
• Received 1 versus ≥2 prior taxane regimens (median OS: 16.2 vs 13.6; Figure 4); and
• Did versus did not receive concurrent ARPi as part of SoC (median OS: 17.8 vs 12.4 months; Figure 5).3

Figure 4. OS by prior treatments in the VISION study3:
Figure 5. OS by concomitant SoC in the VISION study3:

Abbreviations: ADT, androgen deprivation therapy; AE, adverse events; ARPi, androgen receptor pathway inhibitor; ASCO, American Society of Clinical Oncology; CI, confidence interval; ENZAMET, Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer; HR, hazard ratio; ITT, intent-to-treat; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; NSAA, non-steroidal anti-androgen; OR, odds ratio; OS, overall survival; PARP, poly-ADP-ribose polymerase; PCa, prostate cancer; PFS, progression-free survival; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; QoL, quality of life; rPFS, radiographic progression-free survival; SoC, standard of care; SUVmean, mean standardized uptake value.

References: 

1. Davis ID, Martin AJ, Zielinski RR, et al. ENZAMET 5-year update – Xtandi® plus ADT provided a statistically significant Improvement in OS for patients with mHSPC over the active comparator. J Clin Oncol 2022;40(17_Suppl): LBA5004.
2. Hofman MS, Emmett L, Sandhu S, et al. TheraP 3-year update – Comparable OS outcome and improved PFS with 177Lu-PSMA-617 versus cabazitaxel in patients with mCRPC previously treated with docetaxel— Overall survival after median follow-up of 3 years (ANZUP 1603). J Clin Oncol 2022;40(17_Suppl):5000.
3. Vaishampayan N, Morris MJ, Krause BJ, et al. 177Lu-PSMA-617 in PSMA-positive mCRPC patients – Prior and concomitant treatment subgroup analyses of the VISION trial. J Clin Oncol 2022;40(17_Suppl):5001.
4. Davis ID, Martin AJ, Stockletr MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 2019;381:121-131.
5. Hofman MS, Emmett L, Violet J, et al. TheraP: a randomized phase 2 trial of 177Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603). BJU Int 2019;124 Suppl 1:5-13.
6. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet 2021;397:797-804.
7. Buteau J, Martin AJ, Emmett L et al. PSMA PET and FDG PET as predictors of response and prognosis in a randomized phase 2 trial of 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic, castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603). J Clin Oncol 2022;40(6_Suppl):10.
8. Clinicaltrials.gov. NCT0351166. Study of 177Lu-PSMA-617 in metastatic castrate-resistant prostate cancer (VISION). Available at: https://clinicaltrials.gov/ct2/show/NCT0351166. Accessed 18 August 2022.

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