The CARE™ Prostate Cancer Faculty reviews important publications and data throughout the year. Clinically relevant trial updates from recent months are outlined within this report with additional context for how they are expected to impact the Canadian landscape.
- Updated overall survival outcomes in ENZAMET
- ARCHES post hoc analyses
- ARASENS trial
- Ongoing trials: ARASEC and ERADICATE
- Phase III data in high-volume disease
- Assessing intermediate clinical endpoints as potential surrogates for overall survival
- Subgroup analyses of the VISION trial
- Early Phase trial: PRINCE (Phase I trial of combination with pembrolizumab)
- Abiraterone (abi) combined with Olaparib
- Tolerability results from PROpel
This issue was developed with oversight and perspectives provided by CARE™ GU faculty member Dr. Krista Noonan (BC Cancer Surrey, BC).
Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trial information: NCT02446405. Ian D. Davis et al.
- Median follow-up was 68 months, and cut-off date was 19th of January, 2022.
- The hazard rate for death was 30% lower among all those assigned enzalutamide versus control (p<0.0001). Results are shown in the table below.
Table. Results from ENZAMET¹
¹ Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). Ian D. Davis, et al. Journal of Clinical Oncology 2022 40:17_suppl, LBA5004-LBA5004
Enzalutamide added to testosterone suppression, compared with an active comparator of NSAA, provided clinically meaningful improvements in OS for the combined overall cohort, which persisted with an additional 3 years of follow-up. The benefits were more pronounced in patients with low volume disease and were also seen in the subgroup with M1 high volume mHSPC despite the relatively high survival with TS+docetaxel+NSAA.
Video 1 – Dr. Noonan, BCCA provides additional perspective on ENZAMET trial and how treatment of mHSPC is evolving
Additional Canadian Perspectives/Highlights from Video:
- Recap/insights with ENZAMET
- A big question in the community has been around the value of docetaxel in this setting.
- Data presented suggests that the niche may be in high-volume patients and in those with synchronous disease.
- What is the current state of care in Canada?
- Standards have evolved given the significant survival benefits seen with use of triplet therapy (based on PEACE-1) and novel agents (apalutamide, enzalutamide, and darolutamide).
- Moving ahead/what to watch for:
- Additional data for outcomes with darolutamide in low- vs. high-volume is anticipated (refer to the next section for an outline of select ongoing trials).
- More research and data are needed to confirm which patients will derive the most benefit from adding docetaxel to an ARPI.
Association of prostate-specific antigen (PSA) response and overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase 3 ARASENS trial.
Clinical trial information: NCT02799602. Fred Saad et al.
- Median (range) PSA levels at study entry were 30.3 (0.0–9219.0) and 24.2 (0.0–11,947.0) ng/mL, respectively.
- DARO significantly prolonged time to PSA progression (HR 0.255; 95% CI 0.208–0.313; P< 0.0001).
- Undetectable PSA was achieved in more pts receiving DARO (48.7%) vs PBO (23.9%) at 24 weeks, and the rate continued to increase at 36 and 52 weeks in the DARO group to 57.1% and 60.2%, respectively, vs minimal change in the PBO group (25.1% and 26.1%).
- Undetectable PSA levels at any time were achieved in 67.3% in the DARO group and 28.6% in the PBO group.
- For the overall population, OS was improved for pts who achieved undetectable PSA levels vs those who did not at 24 weeks (HR 0.398; 95% CI 0.321–0.493) and 36 weeks (HR 0.351; 95% CI 0.284–0.434).
The combination of DARO + ADT and docetaxel significantly prolonged the time to PSA progression and more patients receiving DARO vs PBO achieved undetectable PSA levels, reflecting strong PSA response over time. In patients with mHSPC, achievement of undetectable PSA at 24 and 36 weeks was associated with improved OS, with risk of death reduced by 60% and 65%, respectively, vs those who did not achieve undetectable PSA at 24 and 36 weeks.
Ongoing Darolutamide mHSPC Trials:
A phase III double-blinded study of early intervention after radical prostatectomy with androgen deprivation therapy with darolutamide versus placebo in men at highest risk of prostate cancer metastasis by genomic stratification (ERADICATE). Clinical trial information: NCT04484818.
- Trial was activated on December 9, 2020 and is currently enrolling patients.
Open-label study of androgen receptor inhibition with darolutamide plus androgen-deprivation therapy (ADT) versus ADT in men with metastatic hormone-sensitive prostate cancer using an external control arm (ARASEC). Clinical trial information: NCT05059236.
- The primary endpoint is PFS. Secondary endpoints are overall survival, radiographic PFS, time to CRPC, complete PSA response rate at 6 months, and safety. Patient recruitment is in progress.
A phase 3 trial of SHR3680 versus bicalutamide in combination with androgen deprivation therapy (ADT) in patients with high-volume metastatic hormone-sensitive prostate cancer (mHSPC). Clinical trial information: NCT03520478. Ding-Wei Ye et al.
- SHR3680 is a novel oral ARI, being investigated vs. bicalutamide (Bica) in high-volume mHSPC.
- SHR3680 significantly reduced the risk of radiographic progression or death than Bica (HR, 0.44; 95% CI, 0.33-0.58; p < 0.0001; median, not reached vs 25.1 mo).
- OS data were immature but an improved OS was observed (HR, 0.58; 95% CI, 0.42-0.80; p = 0.0009).
- Frequencies of adverse events of any cause in any grade were similar between groups.
SHR3680 plus ADT significantly improved rPFS versus Bica plus ADT in patients with high-volume mHSPC, with a desirable safety profile. A new drug application has been submitted to seek approval based on the data presented here.
Assessing intermediate clinical endpoints (ICE) as potential surrogates for overall survival (OS) in men with metastatic hormone-sensitive prostate cancer (mHSPC). Susan Halabi et al.
- Individual patient data (IPD) was obtained from 13/26 eligible randomized trials comparing treatment regimens (androgen deprivation therapy (ADT) or ADT + docetaxel in the control or research arms) in mHSPC.
- Surrogacy of rPFS (time from randomization to radiographic progression or death from any cause) and cPFS (time from randomization to date of radiographic progression, symptoms, initiation of new treatment, or death) as potential ICEs was evaluated.
- Median OS, rPFS and cPFS were 49.4, 26.8 and 25.2 months, respectively.
Both rPFS and cPFS appear to be valid surrogate endpoints for OS. A surrogate threshold effect of 0.82 or higher makes it viable for either rPFS or cPFS to be used as the primary endpoint as a surrogate for OS in phase 3 mHSPC trials and would expedite trial conduct. Validation of these ICEs in trials with drugs having other mechanisms of action is planned.
TheraP: 177Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel—Overall survival after median follow-up of 3 years (ANZUP 1603).
Clinical trial information: NCT03392428. Michael S Hofman et al.
- Authors reported OS outcomes with mature follow-up in trial participants and those initially excluded because of low PSMA-expression or discordant disease on imaging with PSMA-PET and FDG-PET.
- After a median follow-up time of 36 months (data cut-off 31 Dec 2021), death was reported in 70/101 assigned cabazitaxel, 77/99 assigned LuPSMA, and 55/61 excluded after PSMA/FDG-PET.
- Overall survival was similar in those randomly assigned LuPSMA versus cabazitaxel (RMST to 36 months was 19.1 vs. 19.6 months, difference -0.5, 95% CI -3.7 to + 2.7).
- No additional safety signals were identified.
LuPSMA is a suitable option for men with mCRPC progressing after docetaxel, with lower adverse events, higher response rates, improved patient-reported outcomes, and similar OS compared with cabazitaxel. Median survival was considerably shorter for patients excluded on PSMA/FDG-PET due to either low PSMA expression or FDG-discordant disease who would otherwise be eligible for LuPSMA.
[177Lu]Lu-PSMA-617 in PSMA-positive metastatic castration-resistant prostate cancer: Prior and concomitant treatment subgroup analyses of the VISION trial.
Clinical trial information: NCT03511664. Nitin Vaishampayan et al.
- This post hoc exploratory analysis examined rPFS and OS in the context of prior and concomitant cancer-directed treatments (number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents).
- rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups.
- Notably, benefit was seen in patients who had not received a second prior taxanes and regardless of concomitant systemic and radiation therapy as part of SoC.
The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit.
[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.
Phillip Kuo et al.
- This substudy assessed the association between PET parameters and radiographic progression-free survival (rPFS; primary objective), overall survival (OS), objective response rate (ORR), and prostate–specific antigen 50 (PSA50) response.
- In both the whole-body and regional analyses, statistically significant associations of PSMA PET parameters to clinical outcomes were observed.
- Patients in the highest quartile (SUVmean: rPFS, ≥ 10.2; OS, ≥ 9.9) had a median rPFS and OS of 14.1 and 21.4 months, vs 5.8 and 14.5 months for those in the lowest quartile (< 6.0; < 5.7), respectively.
- Absence of PSMA+ lesions in bone, liver, and lymph node, and lower PSMA+ tumor load, were indicators of good prognosis.
Higher SUVmean is strongly associated with improved outcomes with 177Lu-PSMA-617; clinical efficacy for different SUV levels vs the SoC arm is being assessed. Data support use of 68Ga-PSMA-11 PET/CT scan to identify patients who will benefit from PSMA-targeted radioligand therapy.
PRINCE Phase I trial of 177Lu-PSMA-617 in combination with pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC).
Clinical trial information: NCT03658447. Shahneen Sandhu et al.
The combination of 177Lu-PSMA-617 and pembrolizumab had promising activity. Toxicities were generally consistent with those of single-agent 177Lu-PSMA-617 and pembrolizumab and were not clearly augmented by combination use. No new safety concerns were observed.
CCTG PR21: A randomized phase II study of [177lu]lu-PSMA-617 versus docetaxel in patients with metastatic castration-resistant prostate cancer and PSMA-positive disease.
Clinical trial information: NCT04663997. Kim Chi et al.
- Enrollment is encouraged if available at your centre.
More insight on trial data with 177Lu-PSMA-617 from Dr. Noonan:
Additional Canadian Perspectives/Highlights from Video:
- HC approval of LuPSMA is awaited.
- Clinically important notes on TheraP:
- Follow-up was available for 76% of patients.
- There were 14 patients originally randomized to cabazitaxel who dropped out and were put on LuPSMA which would have an influence on the OS endpoint.
- When you do not have proportional hazards, a different statistical strategy is required. In this trial, restricted mean survival time was reported.
- Results support the use of this agent in patients who have progressed on docetaxel or an ARPI.
- Data presented on the VISION subgroup analyses add to the body of evidence showing a consistent benefit across patients and confirm that we should be using Ga-PSMA PET to select patients.
- Having AI capability to calculate SUV mean and education on the importance of including it in reporting with nuclear medicine is needed.
Abiraterone combined with Olaparib
Tolerability of abiraterone (abi) combined with olaparib (ola) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Further results from the phase III PROpel trial.
Clinical trial information: NCT03732820. Antoine Thiery-Vuillemin et al.
- Anemia (n=183) was the most common AE in the ola + abi arm.
- 34% of these 183 events were managed by dose interruption, 23% by dose reduction, and 8% resulted in treatment discontinuation.
- Anemia and pulmonary embolism (PE) were the only Grade ≥3 AEs in ≥5% of pts (anemia: ola + abi, 15.1% vs pbo + abi, 3.3%; PE: 6.5% vs 1.8%, respectively).
- Arterial thromboembolism and cardiac failure AEs were balanced between the treatment arms.
- COVID-19 was reported more frequently with ola + abi (8.3% vs 4.5%).
PROpel demonstrated a predictable safety profile for ola + abi given in combination to pts with 1L mCRPC unselected by HRRm status. The safety profile of abiraterone was not adversely impacted by its combination with olaparib.
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