Dylann Cohn-Emery

Updated data from the phase 3 ENZAMET trial shared during the 2022 ASCO Annual Meeting showed that with over 5 years’ of follow-up enzalutamide (Xtandi) sustained its overall survival (OS) benefit in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The ENZAMET trial (NCT02446405) is an international, cooperative group study comparing enzalutamide with the standard of care as first-line therapy in mHSPC. In the 3-year update of the study, patients with low-volume disease and M1 high-volume disease had more benefit than other groups on the study in addition to the benefit seen in the overall cohort.

“ENZAMET adds to the body of knowledge from several other pivotal trials and now informs best practices for mHSPC,” Ian D. Davis, MBBS, PhD, FRACP, FAChPM, of the Eastern Health Clinical School at Monash University in Box Hill, Australia, said in his presentation.

Previously, patients with low-volume mHSPC did better than those with high-volume disease when testosterone suppression (TS) alone was used, and the same was true in patients with metachronous metastatic disease over synchronous disease. However, combination treatments have shown to be more beneficial than TS alone in varying prognostic groups.

Patients in the ENZAMET trial (n = 1125) were randomized 1:1 to arm A, the control arm consisting of TS plus a standard non-steroidal antiandrogen ([NSAA] bicalutamide, nilutamide, or flutamide), or enzalutamide at 160 mg per day plus TS in arm B. Both arms were evaluated every 12 weeks until progression. Stratification factors included high versus low volume of metastases and use of planned early docetaxel.

At the time of ENZAMET’s interim analysis, the primary end point of OS was met in the combined overall cohort (HR, 0.67; 95% CI, 0.52-0.86; 

There was improvement favoring the triplet of enzalutamide, TS, and docetaxel for prostate-specific antigen (PSA) progression-free survival (PFS) and clinical PFS, which were secondary end points. The clinical benefit outweighed the additional toxicity seen with the addition of enzalutamide, according to patient-reported outcomes. “It was clear that longer follow-up would be required, including, where possible, investigation of differential effects in various prognostic subgroups,” Davis said.

After a median follow-up of 68 months, with a data cutoff date of January 19, 2022, the preplanned analysis point of 470 events was met (n = 476).1 Investigators assessed the effect of enzalutamide based on prognostic grouping and the use of docetaxel. The presence or absence of M1 disease at initial diagnosis and whether or not patients had high-volume disease upon study entry were the 2 binary factors for prognosis for the updated data.

The median OS in the combined cohort was not reached (NR) with enzalutamide versus 73.2 months (95% CI, 64.7-NR) in the control arm (HR, 0.70; 95% CI, 0.58-0.84; 

< .0001). The 5-year survival rate was 67% compared with 57% in arm B and arm A, respectively.

“OS is, of course, influenced by access to and use of subsequent therapy, as well as the study intervention,” Davis explained. “The major difference between the treatment groups for subsequent therapies was the much higher use of enzalutamide or abiraterone [Zytiga] beyond progression in the control group. At the time of the analysis, 76% of those who progressed in the control group were treated with enzalutamide or abiraterone after progression compared to 26% in the enzalutamide group. The survival benefits for enzalutamide were not due to lack of access to effective therapies in the control group.”

In the enzalutamide arm, there was a median of 57.8 months of treatment, for those who remained on treatment, versus 22.6 months on the NSAA arm. Approximately 48% of patients remained on enzalutamide in the experimental arm at 5 years versus 23% of the control arm.

When reviewing these data, other key considerations included that this trial was representative of multiple subgroups of patients, including synchronous and metachronous disease, high- and low-volume disease, and those who did and did not receive docetaxel. The use of docetaxel for study patients was dependent on investigator discretion and assessment of “chemofitness” or predicted benefit. Concurrent docetaxel was planned for up to 6 cycles in 45% of patients, and 108 patients were given 1 cycle of docetaxel and 62 received 2 cycles before randomization.

The OS outcomes by subgroup and other secondary end points were evaluated as exploratory analysis and not formal comparisons due to limited numbers and potential confounders, according to Davis. There were 503 patients who received docetaxel, 602 with high-volume disease, and 683 with synchronous M1 disease. “The message is that no major differences in the effect of enzalutamide were detectable according to baseline characteristics,” Davis stated.

The addition of enzalutamide improved OS for those who received docetaxel, though those who were given early docetaxel did not have as much benefit. Additionally, those who had low-volume mHSPC may have had greater relative benefit over those with high-volume disease, even though both groups benefited. Of note, 71% of patients with high-volume disease also received docetaxel compared with 37% in those with low-volume disease.

There were no significant differences in the percent of patients alive at 5 years for those receiving enzalutamide when looking at baseline characteristics of volume of disease, M1 timing, and docetaxel use. Patients who received concurrent docetaxel who had high volume of disease had a 54% 5-year OS rate with enzalutamide and 51% with NSAA, and those with low volume had a 78% and 67% 5-year OS rate, respectively. The 5-year OS rates were 81% and 66% for those with low-volume mHSPC who did not receive docetaxel with enzalutamide and NSAA treatment, respectively, and 57% and 47% for those with high volume.

NSAA alone had the worst outcomes in the synchronous and metachronous subgroups, regardless of high- or low-volume disease. Enzalutamide and enzalutamide plus docetaxel had similar results, although treatment with concurrent docetaxel most likely has poorer prognosis according to Davis.

Many patients have not had PSA progression and continued on the experimental arm beyond the initial analysis. Enzalutamide added benefit for PSA PFS in all subgroups evaluated.

“This planned analysis after 476 events with a median follow-up of 68 months confirms the benefits of enzalutamide when added to best-practice standard of care,” Davis said. The ENZAMET study strengths were the active control arm, concurrent use of docetaxel, the mix of prognostic groups, and the primary end point of OS. Limitations included that the use of docetaxel was not randomized, and the trial was not powered for formal analysis of the subgroups.

The long-term follow-up confirms the OS benefit of enzalutamide in patients with mHSPC, especially for those with low-volume disease. Across the subgroups, there were no significant differences found with enzalutamide; however, the exploratory analyses suggested additional benefit with the triplet.

“The exploratory analyses raised the hypothesis that the greatest benefit of this triplet therapy with TS plus enzalutamide plus docetaxel may be limited to those with the poorest prognosis disease, particularly synchronous and high-volume metastatic disease. Enzalutamide should be considered in all patients with metastatic disease and especially in those for whom docetaxel is considered unsuitable or unlikely to be beneficial,” Davis concluded.

1. Davis ID, Martin AJ, Zielinski RR, et al; ENZAMET investigators. 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;40(suppl 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004

2. Davis ID, Martin AJ, Stockler MR, et al; 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

Articles

“ENZAMET adds to the body of knowledge from several other pivotal trials and now informs best practices for mHSPC,” said Ian D. Davis, MBBS, PhD, FRACP, FAChPM.

Enzalutamide sustains survival benefit in mHSPC with over 5 years’ follow-up

Initial findings from the phase 2 TRUCE-02 study shared during the 2022 AUA Annual Meeting showed promising activity with the combination of tislelizumab and nab-paclitaxel (Abraxane) in patients with high-risk non–muscle invasive bladder cancer (HR-NMIBC), regardless of PD-L1 expression.

In the study, an open-label, single-arm, phase 2 study (NCT04730232), there was a complete response (CR) rate of 62.5%, which met the primary end point of the trial. Additionally, the high-grade adverse events (AEs) rate was lower than 5% across the study participants.

Previously, the PEANUT trial (NCT03464734) investigating pembrolizumab (Keytruda) plus nab-paclitaxel showed a significant CR rate and low AE rate in the second-line treatment of patients with bladder cancer. The phase 2 KEYNOTE-057 trial (NCT02625961) also demonstrated efficacy and safety with pembrolizumab monotherapy as antitumor treatment in Bacille Calmette-Guérin–unresponsive patients with HR-NMIBC. Previously, tislelizumab showed efficacy in locally advanced or metastatic urothelial carcinoma, and TRUCE-02 investigators are seeking to confirm the benefit of tislelizumab plus nab-paclitaxel.

In this trial, patients with HR-NMIBC that cannot be completely resected received 3 or 4 cycles of tislelizumab on day 1 and nab-paclitaxel on day 2, both at 200 mg intravenously every 3 weeks followed by a multipoint resection biopsy. The primary end point is the patients’ CR rate, and secondary end points included cystectomy-free survival, duration of response, and the number and severity of AEs. The biospecimens of patients’ tumors were sent for analysis by AcornMed panel, which targets 808 cancer-related hotspot genes, before starting treatment. Immunohistochemistry staining was used to measure PD-L1 expression and whole-genome sequencing was used to evaluate urine sediments.

So far, 51 patients have been enrolled in the TRUCE-02 study; 32 patients have completed treatment of 3 or 4 cycles and met the primary end point. There were 20 patients of the 32 total who achieved CR, with a CR rate of 62.5%. Furthermore, 4 patients (12%) experienced a partial response (PR), and 5 (16%) had stable disease. Progressive disease was observed in 3 patients (9%). Currently, 4 patients (12.5%) have proceeded to cystectomy after treatment.

Positive PD-L1 expression was found in 12 (50%) out of the 24 patients who had response of either CR or PR. Three patients out of 8 (38%) who were unresponsive to treatment had positive PD-L1 expression. However, homologous recombination repair mutations may predict favorable prognosis, according to the investigators. The whole-genome sequencing results of patients’ tumor tissue and urine were considered uniform.

In patients receiving the tislelizumab combined with nab-paclitaxel, the most common low-grade treatment-related AEs included alopecia in 81% and fatigue in 34%. All other AEs were seen in 7% of patients or fewer. Immune-related severe AEs included cytokine release syndrome in 1 patient (3%) and 1 patient (3%) with popular and pustular rash.

The median age on the trial was 67 years (range, 44-85), and there were 25 male patients recruited. Patients had to have an ECOG performance status of 0 to 2. If patients had previously received PD-1, PD-L1, or CTLA-4 antibodies, or other immunotherapies previously, they could not be enrolled on the trial.

1. Hu H, Niu Y, Wang H, et al. Update of TRUCE-02: an open label, single-arm, phase 2 study of tilelizumab combined with nab-paclitaxel for high-risk non-muscle-invasive urothelial bladder carcinoma (HR-NMIBC) which is not completely resectable. Presented at: 2022 American Urological Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract MP59-19.

Patients in the study had tumors that were not completely resectable.

Tislelizumab plus nab-paclitaxel shows promise in high-risk NMIBC

Initial data from the phase 2 TRUCE-01 trial presented at the 2022 AUA annual Meeting showed that the neoadjuvant combination of the PD-1 inhibitor tislelizumab and nab-paclitaxel (Abraxane) induced a high rate of pathologic complete response (pCR) in patients with muscle-invasive bladder cancer (MIBC).

Investigators of the single-arm, open-label phase 2 trial (NCT04730219) did not observe an increase in adverse events (AEs) or a correlation of PD-L1 expression with the efficacy of the neoadjuvant therapy. However, high tumor mutation burden (TMB) did show a correlation to response with the combination.

Neoadjuvant treatment with immune checkpoint inhibitors showed comparable efficacy and fewer AEs than chemotherapy in the PURE-01 trial (NCT02736266) of pembrolizumab (Keytruda) and the ABACUS trial (NCT02662309) of atezolizumab (Tecentriq) in MIBC. Although, at this point, the efficacy of combination chemotherapy and PD-1/PD-L1 inhibition has not been determined. This study in patients with MIBC is evaluating the PD-1 inhibitor tislelizumab combined with second-line chemotherapy in the neoadjuvant setting.

In the ongoing TRUCE-01 trial, patients with stage T2-4aN0-1M0 disease were given 200 mg of tislelizumab on day 1 and 200 mg of nab-paclitaxel on day 2 every 3 weeks for 3 cycles, followed by complete transurethral resection of bladder tumor (cTURBT) or radical cystectomy. The Dako 22C3 pharmDx assay was used to conduct biomarker analysis on PD-L1 expression using combined positive score. TMB was also evaluated for the analysis. The primary end point was pCR, defined as the absence of a viable tumor (pT0N0M0).

Thirty patients completed this regimen of neoadjuvant tislelizumab plus nab-paclitaxel and received a radical cystectomy (n = 9) or cTURBT (n = 21) between July 2020 and July 2021. A total of 16 patients achieved pCR (53.3%; 95% CI, 36.7%-73.3%). Downstaging to pT less than 2 occurred in 21 patients (70%; 95% CI, 53.3%-86.7%), which was a secondary end point in this trial.

Patients who responded to therapy had a higher TMB level than those who did not respond (

 = .067). No significant correlation was observed between PD-L1 expression and the efficacy of the tislelizumab/nab-paclitaxel combination. Eight patients with PD-L1–positive expression achieved pT0 versus 8 patients with PD-L1–negative expression (

In terms of AEs, 1 patient experienced grade 3 rash and 1 patient had grade 4 acute renal failure. After corticosteroid treatment, both patients recovered. Alopecia was observed in 96% of patients, fatigue in 63%, hyperglycemia in 33%, rash in 27%, fever in 17%, and creatinine increase in 13% were the most common grade 1 or 2 AEs.

TRUCE-01 is currently enrolling adult patients with histopathologically confirmed urothelial carcinoma who are planning to receive a cTURBT or radical cystectomy. Patients must have an ECOG performance status of 0 to 2 and an expected survival over more than 12 weeks. Patients who have previously received a PD-1, PD-L1, or CTLA-4 antibody or other immunotherapies are not able to participate in this trial. The trial is located at Tianjin Medical University Second Hospital in Tianjin, China.

1. Hu H, Niu Y, Wang H, et al. Update of TRUCE-01: neoadjuvant tislelizumab combined with nab-paclitaxel for muscle-invasive urothelial bladder carcinoma. Presented at: 2022 American Urological Association Annual Meeting; May 13-16, 2022; New Orleans, LA. Abstract PD10-07.

The neoadjuvant combination of the PD-1 inhibitor tislelizumab and nab-paclitaxel induced a high rate of pathologic complete response in patients with muscle-invasive bladder cancer.  

Neoadjuvant chemoimmunotherapy shows promise in MIBC

Frontline therapy with nivolumab (Opdivo) plus cabozantinib (Cabometyx) sustained its overall survival (OS) benefit versus sunitinib (Sutent) in patients with clear cell metastatic or advanced renal cell carcinoma (RCC), according to the final OS analysis from the phase 3 CheckMate 9ER trial.

Thomas Powles, MD, PhD, professor of genitourinary oncology and director of Barts Cancer Centre at St. Bartholomew's Hospital, discussed the updated findings at the 2022 American Society of Clinical Oncology Genitourinary Cancers Symposium.

Furthermore, the combination demonstrated sustained progression-free survival (PFS) and objective response rate (ORR) benefit at a minimum of 2 years of follow-up. More patients receiving nivolumab/cabozantinib had tumor shrinkage benefit than those receiving sunitinib across the 4 organ types accessed on the trial as well.

“With this extended median follow-up of 33 months, nivolumab/cabozantinib provided improved survival versus sunitinib in the final OS analysis,” Powles said in his presentation. “With nivolumab/cabozantinib versus sunitinib, median PFS, ORR, and complete response rates were approximately double.”

The original results of the open-label, randomized phase 3 CheckMate 9ER trial (NCT03141177) showed superiority with first-line nivolumab/cabozantinib versus sunitinib, with 10.6 months of minimum follow-up.

 Patients with treatment-naïve clear cell RCC were assigned 1:1 to nivolumab/cabozantinib (n = 323) at 240 mg every 2 weeks and 40 mg once daily, respectively, versus sunitinib (n = 328) at 50 mg once daily for 4 weeks of each 6-week cycle.

The primary end point was PFS by blinded independent central review (BICR) in the ITT population, and secondary end points included OS, ORR, and safety. There was a preplanned final OS analysis planned when 254 event were observed. Post hoc exploratory analyses included maximal reduction of target lung, lymph node, kidney, and liver lesions evaluated per BICR.

After 32.9 months median follow-up (range, 25.4-45.4), the hazard ratio for nivolumab/cabozantinib versus sunitinib was 0.70 (95% CI, 0.55-0.90).1 Nivolumab/cabozantinib showed a median OS of 37.7 months (95% CI, 35.5-not evaluable [NE]) compared with 34.3 months (95% CI, 29.0-NE) for sunitinib.

The median PFS for those receiving nivolumab/cabozantinib was also improved versus sunitinib, at 16.6 months (95% CI, 12.8-19.8) and 8.3 months (95% CI, 7.0-9.7), respectively (HR, 0.56; 95% CI, 0.46-0.68).

Additionally, patients given nivolumab/cabozantinib achieved a confirmed ORR of 55.7% (95% CI, 50.1%-61.2%) compared with 28.4% (95% CI, 23.5%-33.6%) for those given sunitinib. Complete response rates were almost doubled with nivolumab/cabozantinib versus sunitinib, at 12.4% and 5.2%, respectively. The median time to response was shorter (2.8 months vs 4.2 months) and median duration of response was longer (23.1 months vs 15.1 months) for 180 patients who responded on the nivolumab/cabozantinib arm than the 93 who responded on the sunitinib arm.

Even though there were similar median diameters of target lesions at baseline between nivolumab/cabozantinib and sunitinib, the exploratory post hoc analysis showed a higher proportion of patients who experienced reductions in target lesions with nivolumab/cabozantinib. In bone (55.6% vs 20.0%, respectively), lymph node (74.4% vs 47.8%), lung (75.9% vs 46.4%), liver (47.7% vs 33.3%), and kidney (45.2% vs 29.7%) target lesions, a reduction of 30% or more was observed.

Ninety-two patients (28.8%) receiving nivolumab/cabozantinib remained on therapy compared with 46 patients (14.4%) receiving sunitinib. The median duration of therapy was 21.8 months (range, 0.2-42.0) versus 8.9 months (range, 0.5-41.4), respectively.

No new safety signals were observed in with longer follow-up. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 65.0% of those on the nivolumab/cabozantinib arm and 54.1% on the sunitinib arm. The most common grade 3 TRAEs occurring in 20% or more of all treated patients included hypertension, palmar-plantar erythrodysethesia, and diarrhea. TRAEs led to discontinuation of nivolumab, cabozantinib, or both in 27.2% of patients, and discontinuation of sunitinib 10.3% of patients. Since the original data cutoff, only 1 additional death related to treatment was observed with sunitinib, and none with nivolumab/cabozantinib.

“These results continue to support the use of nivolumab/cabozantinib as a first-line treatment option for patients with advanced RCC,” Powles concluded.

1. Thomas P, Toni KC, Mauricio B, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: Nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. 

2022;40(suppl 6):350. doi:10.1200/JCO.2022.40.6_suppl.350

2. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. 

 2021;384(9):829-841. doi:10.1056/NEJMoa2026982

The final overall survival analysis from the phase 3 CheckMate 9ER trial continued to show a benefit with frontline nivolumab/cabozantinib versus sunitinib in patients with advanced renal cell carcinoma.

Dylann Cohn-Emery

Articles

Enzalutamide sustains survival benefit in mHSPC with over 5 years’ follow-up

Tislelizumab plus nab-paclitaxel shows promise in high-risk NMIBC

Neoadjuvant chemoimmunotherapy shows promise in MIBC

Nivolumab/Cabozantinib survival benefit in RCC sustained with extended follow-up