Gina Mauro

Prior local therapy had no bearing on the survival, radiographic progression-free, response, and undetectable PSA benefits conferred when adding enzalutamide (Xtandi) to androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

The findings, which came from a post-hoc analysis of the phase 3 ARCHES trial (NCT02677896) presented during the 2022 AUA Annual Meeting,1 also showed that the improvements with enzalutamide were seen across all patient subgroups and cascaded to symptomatic skeletal event (SSEs), new antineoplastic therapy, castration resistance, and deterioration of urinary symptoms vs placebo plus ADT.

For example, in patients who did receive prior local treatment, the median overall survival (OS) was not reached with enzalutamide/ADT (n = 131) nor placebo/ADT (n = 141) at a median follow-up of 44.6 months (HR, 0.56; 95% CI, 0.34-0.92; 

 = .02). In the subgroup of those who did not receive prior local treatment, the median OS was also not reached in both arms (HR, 0.68; 95% CI, 0.54-0.86; 

“This post-hoc analysis demonstrated the long-term survival benefit of enzalutamide plus ADT versus placebo plus ADT in patients with mHSPC who received prior local therapy, supporting the utility of enzalutamide irrespective of receipt of local therapy,” lead study author Neal D. Shore, MD, director of CPI, of Carolina Urologic Research Center, and coinvestigators, wrote in a poster presented during the meeting. “These results are consistent with those previously reported in the overall population of ARCHES.”

In December 2019, the FDA approved enzalutamide for use in combination with ADT for the treatment of patients with mHSPC.

 The decision was based on earlier findings of the ARCHES trial, in which 1150 patients were randomized 1:1 to receive enzalutamide at 160 mg daily plus ADT or placebo plus ADT. Stratification factors included disease volume and prior docetaxel use.

Results showed that the enzalutamide arm significantly improved radiographic progression-free survival (rPFS) and OS, as well as key secondary end points, vs placebo/ADT in this patient population.

 A long-term OS benefit was also reported in a subsequent analysis.

ARCHES was unblinded after the primary analysis to permit patients who were randomized to placebo/ADT to cross over to enzalutamide/ADT in an open-label extension phase of the research.

In the post-hoc analysis of ARCHES, investigators sought to explore the effect of enzalutamide plus ADT compared with placebo/ADT on the OS of patients who received prior local treatment to the prostate. To be eligible for this analysis, patients must have received local therapy, which was defined as prior radical prostatectomy (RP) and/or radiation (RT) to the prostate in the definitive, adjuvant, or salvage setting.

Enrollment was based on investigator-assessed metastases. Following study entry, metastases were examined by a blinded independent central review. Moreover, prior ADT and up to 6 cycles of prior docetaxel were allowed. Those with disease progression prior to randomization while receiving ADT and/or docetaxel were excluded.

The overall ARCHES population included 1150 patients with mHSPC. Of these patients, 272 had received prior local therapy; 131 patients were on the enzalutamide arm and had received radical prostatectomy (n = 37), radiation (n = 59), or both (n = 35) and 141 patients were on the placebo arm who were previously given RP (n = 45), RT (n = 52), or both (n = 44).

A total 184 patients (31.9%) who were randomized to placebo/ADT remained progression free and gave informed consent crossed over following unblinding of the study. Of these, 180 patients received enzalutamide/ADT. The median time to crossover was 21.5 months.

Baseline characteristics were mostly similar between the 2 groups. However, at study enrollment, a greater proportion of patients who did not receive local treatment had distant metastatic disease (M1) at initial diagnosis (enzalutamide/ADT arm, 84.7%; placebo/ADT, 78.6%) as well as an ECOG performance status of 1 (enzalutamide/ADT, 76.7%; placebo/ADT, 74.9%) and a Gleason score of 8 or higher (enzalutamide/ADT, 77.4%; placebo/ADT, 72.9%), vs those who did have local therapy.

Additional results showed that, in both patients with and without prior local therapy, rPFS was improved with enzalutamide/ADT (with prior treatment, HR, 0.44; without prior treatment, HR, 0.38), as well as time to PSA progression (HR, 0.34 and HR, 0.27, respectively), time to first SSE (HR, 0.39 and HR, 0.52), time to castration resistance (HR, 0.42 and HR, 0.39), time to new antineoplastic therapy (HR, 0.36 and HR, 0.40), time to deterioration of urinary symptoms (HR, 0.90 and HR, 0.88), and time to pain progression (HR, 0.88 and HR, 0.98).

Of patients who had detectable PSA at baseline, more patients treated with enzalutamide plus ADT achieved undetectable PSA (<0.2 ng/mL) compared with placebo plus ADT in both the prior treatment (84.5%) and no prior treatment. Moreover, there was a greater rate difference in those who had not received local treatment (rate difference [RD], 56.9%; 95% CI, 51.5-62.3; 

 <.0001) compared with those who had received it (RD, 39.2%; 95% CI 27.3-51.0; 

Objective response rates (ORRs) were also higher in the enzalutamide/ADT arm compared with placebo/ADT in both subgroups. Enzalutamide/ADT elicited a 72.4% ORR in patients with prior treatment and 83.2% in those without; these rates were 59.2% and 61.4%, respectively, with placebo/ADT.

Investigators also noted that there were no safety differences between the prior local therapy and no prior local treatment subgroups, and that the safety profiles were comparable to what had been observed in the overall study population.

Shore ND, Iguchi T, Villers A, et al. Overall survival in patients with metastatic hormone-sensitive prostate cancer treated with enzalutamide or placebo plus androgen deprivation therapy who had prior local therapy: post hoc analysis of the phase 3 ARCHES trial. Presented at: 2022 AUA Annual Meeting, May 13-18, 2022; New Orleans, LA. Abstract 22-5476.

Xtandi (Enzalutamide) approved by US FDA for the treatment of metastatic castration-sensitive prostate cancer. News release. Pfizer. December 16, 2019. Accessed May 14, 2022. https://bit.ly/2tpujIV

Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase iii study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. 

 2019;37(32):2974-2986. doi:10.1200/JCO.19.00799.

Armstrong AJ et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer.

. Published online April 14, 2022. doi:10.1200/JCO.22.00193

Articles

The findings came from a post-hoc analysis of the phase 3 ARCHES trial.

Enzalutamide/ADT survival benefit in mHSPC unaffected by prior local therapy

Long-term data from the phase 3 JAVELIN Bladder 100 trial continued to show an overall survival (OS) boost with frontline avelumab (Bavencio) maintenance in patients with metastatic urothelial cancer who received first-line chemotherapy.

With an additional 19 months of follow-up, the median OS with avelumab plus best supportive care (BSC) was 23.8 months (95% CI, 19.9-28.8) compared with 15.0 months (95% CI, 13.5-18.2) with BSC alone (hazard ratio [HR], 0.76; 95% CI, 0.631-0.915; 

 = .0036). The 2- and 3-year OS rates with avelumab/BSC were 49.8% and 36.0%, respectively; these rates were 38.4% and 29.8%, respectively, in the BSC-alone arm.

Additional data, which were presented during the 2022 Genitourinary Cancers Symposium, showed that the investigator-assessed progression-free survival (PFS) was 5.5 months (95% CI, 4.2-7.2) with avelumab/BSC and 2.1 months (95% CI, 1.9-3.0) with BSC alone, translating to a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.457-0.645; 

 <.0001). The 2- and 3-year PFS rates were 23.4% and 15.9%, respectively, with avelumab/BSC, and 7.1% and 5.3%, respectively, with BSC alone.

Lead study author Thomas Powles, MBBS, MRCP, MD, explained in a poster presentation during the meeting that no new safety signals were identified with the combination.

“In summary, these data show this consistent survival signal, a HR of 0.76 remains clinically meaningful, and this remains the standard of care for those patients with metastatic urothelial cancer who receive first-line chemotherapy, sequencing maintenance avelumab remains attractive for these patients, across broad subgroups of patients, with no new safety signals,” Powles, who is director of Barts Cancer Institute, said.

Earlier data from JAVELIN Bladder 100 led to the FDA approval of frontline maintenance avelumab plus BSC in June 2020 for use in patients with advanced urothelial cancer that did not progress on frontline platinum-based chemotherapy. At the earlier analysis, the median OS was 21.4 months (95% CI, 18.9-26.1) with the addition of avelumab and 14.3 months (95% CI, 12.9-17.9) with BSC alone, leading to a 31% reduction in the risk of death (HR, 0.69; 95% CI; 0.56-0.86; 1-sided 

In the phase 3 JAVELIN Bladder 100 trial, 700 patients with unresectable locally advanced or metastatic urothelial cancer were randomized 1:1 to receive avelumab plus BSC (n = 350) or BSC alone (n = 350) until disease progression, unacceptable toxicity, or withdrawal. A total of 358 patients had PD-L1–positive disease.

To be eligible for participation, patients must have had a complete response (CR), partial response (PR), or stable disease (SD) with standard frontline chemotherapy with either cisplatin/gemcitabine or carboplatin/gemcitabine for 4 to 6 cycles.

Stratification factors included best response to frontline chemotherapy (CR or PR vs SD) and metastatic site (visceral vs nonvisceral) when initiating frontline chemotherapy.

The primary end point of the trial was OS in all randomized patients and in the PD-L1–positive population; secondary end points included PFS, objective response per RECIST v1.1 criteria, and safety.

The updated analysis includes at least 2 years of follow-up in all patients, bringing it to a median follow-up of 38 months. The data cutoff date was June 4, 2021.

Further findings showed that the OS benefit was observed across most prespecified subgroups and was found irrespective of site of metastases (visceral: HR, 0.91; 95% CI, 0.713-1.163; non-visceral: HR, 0.60; 95% CI, 0.451-0.798) and type of chemotherapy used (gemcitabine/cisplatin: HR, 0.78; 95% CI, 0.607-1.008; gemcitabine/carboplatin: HR, 0.70; 95% CI, 0.523-0.929; gemcitabine/carboplatin/cisplatin: HR, 0.69; 95% CI, 0.294-1.639). The benefit was not seen in those from Australia (HR, 1.29; 95% CI, 0.697-2.398) and those with liver lesions at baseline (HR, 0.95; 95% CI, 0.585-1.541).

It was also reported that more patients in the BSC-alone arm received subsequent anticancer therapy. Of all patients (n = 700), 52.9% of patients in the avelumab/BSC arm discontinued and received subsequent therapy with a PD-1/PD-L1 inhibitor (11.4%), FGFR inhibitor (2.9%), or another drug (50.6%). In the BSC-alone arm, 72.0% of patients discontinued treatment and went onto a PD-1/PD-L1 inhibitor (53.1%), FGFR inhibitor (3.7%), or another drug (44.6%). Moreover, 12.3% and 2.9% of patients in the investigative and control arms, respectively, were still receiving study treatment.

Of the subgroups who received subsequent therapy (n = 437), 21.6% of those on the avelumab arm (n = 185) were treated with a PD-1/PD-L1 inhibitor, 5.4% a FGFR inhibitor, and 95.7% another drug; these rates were 73.8%, 5.2%, and 61.9%, respectively, in the BSC-alone arm (n = 252).

For patients who discontinued study treatment due to progressive disease (n = 484), 75.6% of those on avelumab/BSC (n = 209) discontinued and received subsequent treatment with a PD-1/PD-L1 inhibitor (12.9%), FGFR inhibitor (4.8%), or another drug (72.2%). Of those in this subgroup who were treated with BSC alone (n = 275), 81.8% of patients discontinued and received subsequent therapy with a PD-1/PD-L1 inhibitor (60.4%), FGFR inhibitor (4.0%), or another drug (50.5%).

Regarding safety, Powles noted that the long-term safety profile with avelumab, which was analyzed in patients receiving the combination for at least 12 months, was consistent with prior studies of the single-agent checkpoint inhibitor. All-grade and grade 3 or higher treatment-emergent adverse effects (TEAEs) that occurred after at least 12 months of treatment were reported in 86.4% of patients who received avelumab/BSC (n = 118) and 47.5% were grade 3 or higher; these effects occurred with onset at any time (n = 344) in 98.3% of patients; 53.8% of patients had grade 3 or higher TEAEs with onset at any time.

Additionally, any-grade and grade 3 or higher treatment-related AEs (TRAEs) occurring after at least 12 months of treatment occurred in 50.0% and 11.9% of patients; these rates were 78.2% and 19.5%, respectively, at any time.

Also, as onset after at least 12 months of treatment, serious TEAEs occurred in 23.7% of patients and serious TRAEs were reported in 5.1% of patients; 36.4% experienced TEAEs that led to interruption of avelumab and 11.0% had TEAEs that led to discontinuation. TEAEs and TRAEs that led to death occurred in 2.5% and 0.8% of patients, respectively. All-grade infusion-related reactions were reported in 3.4% of patients.

For onset of AEs that occurred at any time, serious TEAEs occurred in 30.5% and serious TRAEs were reported in 10.2% of patients; 45.3% of patients had TEAEs that led to avelumab interruption and 14.2% had TEAEs that led to discontinuation. TEAEs and TRAEs that led to death occurred in 2.0% and 0.6% of patients, respectively. All-grade infusion-related reactions were reported in 21.8% of patients.

The most common TEAEs with onset at this time point was urinary tract infection and diarrhea (n = 15; 12.7% each). One patient did experience a TRAE of immune-mediated nephritis after at least 1 year of the combination that led to death.

1. Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. 

. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487

2. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. 

. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788

Long-term data from the phase 3 JAVELIN Bladder 100 trial continued to show an overall survival (OS) boost with frontline avelumab maintenance in patients with metastatic urothelial cancer.

Avelumab maintenance benefit in urothelial carcinoma sustained with extended follow-up

Results from the placebo-controlled phase 3 PROpel trial showed that adding the PARP inhibitor olaparib (Lynparza) to frontline abiraterone acetate (Zytiga) significantly improved radiographic progression-free survival (rPFS) in patients with metastatic castration-resistant prostate cancer (mCRPC).

Data presented during the 2022 ASCO Genitourinary Cancers Symposium showed that the median investigator-assessed rPFS was 24.8 months with olaparib/abiraterone vs 16.6 months with placebo/abiraterone translating to a 34% reduction in the risk of radiographic disease progression or death (HR, 0.66; 95% CI, 0.54-0.81; 

 <.0001). The 1- and 2-year rPFS rates were 71.8% and 51.4% in the olaparib/abiraterone arm, respectively; these rates were 63.4% and 33.6% with placebo/abiraterone, respectively.

When evaluated by blinded independent central review, the median rPFS with olaparib/abiraterone was 27.6 months vs 16.4 months with placebo/abiraterone, leading to a 39% reduction in the risk of radiographic disease progression or death (HR, 0.61; 95% CI, 0.49-0.74; 

 <.0001). The 1- and 2-year rPFS rates with olaparib plus abiraterone were 73.8% and 53.7%, respectively. In the placebo/abiraterone arm, these rates were 60.6% and 34.1%, respectively.

Lead study author Fred Saad, MD, FRCS, said that PROpel is the first combination approach to deliver consistent clinical benefits for patients in the first-line mCRPC setting, irrespective of homologous recombination repair (HRR) mutation status.

“This benefit led to what I think is the longest rPFS we have seen to date in metastatic CRPC beyond 2 years,” Saad, who is professor and chairman of urology and director of Genitourinary Oncology at the University of Montreal Hospital Center, as well as the Raymond Garneau Chair in Prostate Cancer Research and director of Clinical Research and the Molecular Oncology Research Laboratory in Prostate Cancer, said in a presentation during the meeting.

Patients with mCRPC who are treated in the frontline setting have a median survival of approximately 3 years in clinical trial settings, Saad noted, adding that about half of patients in real-world practice only receive 1 line of active treatment. Here, the median survival is less than 2 years, underscoring an unmet need to improve outcomes in the up-front setting.

Previously, data with olaparib in mCRPC have shown encouraging results. The phase 3 PROfound trial (NCT02987543) demonstrated significantly prolonged rPFS and overall survival (OS) in patients with mCRPC following a next-generation hormonal agent (NHA) with HRR gene alterations.

 Additionally, a phase 2 trial (NCT01972217) of olaparib and abiraterone showed prolonged investigator-assessed rPFS vs placebo/abiraterone in patients with mCRPC following treatment with docetaxel, regardless of HRR status (HR, 0.65; 95% CI, 0.44-0.97; 

In the international, double-blind, phase 3 PROpel trial (NCT03732820), investigators randomized patients with mCRPC in the first-line setting 1:1 to receive olaparib at 300 mg twice daily plus abiraterone at 1000 mg daily (n = 399) or placebo and abiraterone at 1000 mg daily (n = 397). Patients could have received docetaxel in the metastatic hormone-sensitive prostate cancer (mHSPC) setting, but no prior abiraterone was allowed. Other NHAs were permitted if they were stopped at least 12 months prior to study enrollment. Patients also had ongoing androgen deprivation therapy and an ECOG performance status of 0 or 1.

Stratification factors included site of distant metastases (bone-only vs visceral vs other) and prior taxane in the mHSPC setting (yes vs no).

The primary end point was investigator-assessed rPFS, with OS as a secondary end point. Additional outcome measures included time to first subsequent therapy or death (TFST), time to second progression or death (PFS2), objective response rate (ORR), HRR mutation prevalence (retrospective testing), health-related quality of life, and safety and tolerability.

Baseline characteristics were well-balanced between the 2 arms. The median age was 69.5 years (range, 43-91), and most patients had an ECOG performance status of 0 (70.1%). Of note, symptomatic patients (Brief Pain Inventory-Short Form ≥4 and/or opiate use) comprised 25.8% and 20.2% of olaparib- and placebo-treated patients, respectively; 22.5% of patients had received docetaxel at the mHSPC stage.

Additionally, patients either had HRR mutations (27.8% with olaparib vs 29.0% with placebo), non-HRR mutations (69.9% vs 68.8%, respectively), or unknown HRR mutation status (2.3% each). The median PSA was 17.90 ug/L (interquartile range [IQR], 6.09-67.00) with olaparib/abiraterone and 16.81 ug/L (IQR, 6.26-53.30) with placebo/abiraterone. Most metastases occurred in the bone at 87.5% and 85.4% of patients, respectively.

Additional findings showed that the rPFS benefit was observed across all prespecified subgroups, including age (<65 years, HR, 0.51; 95% CI, 0.35-0.75; ≥65 years, HR, 0.78; 95% CI, 0.62-0.98), site of distant metastases (bone-only, HR, 0.73; 95% CI, 0.54-0.98; visceral, HR, 0.62; 95% CI, 0.39-0.99; other, HR, 0.62; 95% CI, 0.44-0.85) prior docetaxel (yes, HR, 0.61; 95% CI, 0.40-0.92; no, HR, 0.71; 95% CI, 0.56-0.89) and HRR mutation status (HRR mutant, HR, 0.50; 95% CI, 0.34-0.73; non–HRR mutant, HR, 0.76; 95% CI, 0.60-0.97).

“We did do a global interaction test, which was not significant,” Saad added.

OS data, which were at 28.6% maturity, showed that the median OS was not reached in either arm but trended toward improved survival with olaparib/abiraterone vs placebo/abiraterone (HR, 0.86; 95% CI, 0.66-1.12; prespecified 2-sided alpha 

TFST also was favored with the addition of olaparib. The median TFST was 25.0 months in the olaparib/abiraterone arm compared with 19.9 months with placebo/abiraterone (HR, 0.74; 95% CI, 0.61-0.90; 

 = .004). Furthermore, the median PFS2 was not reached in either arm, but supported longer-term benefit with olaparib/abiraterone (HR, 0.69; 95% CI, 0.51-0.94; 

When evaluated for response, the ORR with olaparib plus abiraterone was 58.4% with a 4.3% complete response (CR) rate and a 54.0% partial response (PR) rate. The stable disease (SD) rate was 26.1% and the progressive disease (PD) rate was 13.7%. In the placebo/abiraterone arm, the ORR was 48.1%, which comprised a 6.3% CR rate and a 41.9% PR rate; the SD and PD rates were 28.1% and 19.4%, respectively. The odds ratio in ORR between olaparib/abiraterone and placebo/abiraterone was 1.60 (95% CI, 1.02-2.53; 

Saad noted that 40.3% of the overall study population had measurable disease via RECIST v1.1 criteria at baseline.

Regarding safety, adverse effects (AEs) occurred in 97.2% and 94.9% of olaparib/abiraterone- and placebo/abiraterone-treated patients, respectively; grade 3 or higher AEs occurred in 47.2% and 38.4% of patients, respectively. AE-related deaths occurred in 4.0% (n = 16) of those on the olaparib arm compared with 4.3% (n = 17) of patients on the placebo arm.

Dose interruptions and reductions occurred in 44.7% and 20.1% of patients who received the addition of olaparib; these rates were 25.3% and 5.6% for those on the placebo arm.

Additionally, more patients discontinued olaparib due to an AE (13.8%) compared with 7.8% of patients receiving placebo. A total of 8.5% and 8.8% of patients in each arm, respectively, discontinued abiraterone due to an AE.

There were no cases reported of myelodysplastic syndrome or acute myeloid leukemia, and the incidence of new primary cancers and pneumonitis were balanced between the 2 arms, Saad said.

The AE profiles were consistent with the known toxicity profiles of the individual agents. The most common all-grade and grade 3 or higher AE with olaparib was anemia (46.0% and 15.1%, respectively). In the placebo arm, this occurred in 16.4% and 3.3% of patients, respectively.

Cardiac failure occurred at similar rates between the 2 arms at 1.5% with olaparib and 1.3% with placebo; arterial thromboembolic events were also similar at 2.0% and 2.5%, respectively. However, numerically higher venous thromboembolic events were reported for olaparib/abiraterone (7.3%) vs placebo/abiraterone (3.3%), with pulmonary embolism being the most reported venous thromboembolic event (6.5% vs 1.8%, respectively). Pulmonary embolism events were mostly incidental findings via CT scans, and Saad added that this did not lead to treatment discontinuation with either olaparib or abiraterone.

Quality of life was also found to be comparable between the 2 groups.

1. Saad F, Armstrong AJ, Thiery-Vuillemin A, et al. PROpel: phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). 

. 2022;40(suppl 6):11. doi:10.1200/JCO.2022.40.6_suppl.011

2. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer. 

. 2020;383(24):2345-2357. doi:10.1056/NEJMoa2022485

3. Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. 

. 2018;19(7):975-986. doi:10.1016/S1470-2045(18)30365-6

The phase 3 PROpel trial showed that adding the PARP inhibitor olaparib to abiraterone acetate in the frontline setting significantly improved radiographic progression-free survival versus placebo plus abiraterone in patients with metastatic castration-resistant prostate cancer. 

Olaparib addition to abiraterone delays progression in frontline mCRPC

Data presented at the 2021 American Urological Association Annual Meeting showed that adjuvant pembrolizumab (Keytruda) improved disease-free survival (DFS) vs placebo across all prespecified subgroups, including region, type of nephrectomy, sarcomatoid features, disease risk category, tumor grade, and PD-L1 status.

The benefit was most significantly pronounced in patients who underwent partial nephrectomy (HR, 0.22; 95% CI, 0.05-1.04) and those who had M1 no evidence of disease (NED; HR, 0.29; 95% CI, 0.12-0.69). The data were derived from the phase 3 KEYNOTE-564 trial (NCT03142334).

“Although numbers of participants with certain disease risk features were small, the DFS benefit was consistent across subgroups,” lead study author Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, as well as Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, said in a virtual presentation during the meeting. “Safety results were in line with expectations and no new safety signals were observed.”

Earlier findings from the KEYNOTE-564 study were 

presented during the 2021 ASCO Annual Meeting

 to a new supplemental biologics license application for adjuvant pembrolizumab as a treatment for patients with RCC who are at intermediate-high or high risk of recurrence after nephrectomy or following nephrectomy and resection of metastatic lesions.

 The agency is expected to decide on the application by December 10, 2021.

In the double-blind, multicenter, phase 3 KEYNOTE-564 study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Specifically, patients’ disease had to meet criteria that categorized them as intermediate-high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; high-risk pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with NED after surgery.

Stratification factors included metastatic status (M0 vs M1 NED), as well as ECOG performance status (0 vs 1) and region (US vs non-US), both in the M0 group only.

To be eligible for enrollment, patients must have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic therapy, had to have an ECOG performance status of 0 or 1, and a tissue sample must have been obtainable for PD-L1 testing.

All patients underwent 1:1 randomization to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

The primary end point of the trial was investigator-assessed DFS; secondary end points were overall survival (OS) and safety.

The first prespecified interim analysis was planned following approximately 265 DFS events and a 12-month minimum follow-up. Following a minimum 15-month follow-up, 260 DFS events had occurred, and 51 OS events occurred. DFS and OS were estimated via Kaplan-Meier.

The median age of study participants was 60 years (range, 25-84), 71% of patients were male, and 73.5% had an ECOG performance status of 1. Moreover, 25.95% of patients were from North America, 37.7% were from the European Union, and 37.3% were from the rest of world. Most patients (92.4%) underwent radical nephrectomy and 83.7% had absent sarcomatoid features.

The majority of patients (86.5%) had M0 intermediate-high risk disease, 7.6% had M0 high-risk disease, and 5.8% had M1 NED. Moreover, 88.6% of patients had a primary tumor stage of T3; 3.5%, 30.4%, 43.5%, 22.3% of patients had tumor grade 1, 2, 3, and 4, respectively. Additionally, 93.8% of patients had N0 disease. Seventy-five percent of patients had a PD-L1 combined positive score of at least 1.

The data cutoff date was December 14, 2020. At a median follow-up of 24.1 months (range, 14.9-41.5), the median DFS in the intent-to-treat population was not reached with either pembrolizumab (n = 496) or placebo (n = 498) per investigator assessment (HR, 0.68, 95% CI, 0.53-0.87; 

 = .0010). The estimated 1-year DFS rates were 85.7% and 76.2% with pembrolizumab and placebo, respectively; the 2-year rates were 77.3% and 68.1%, respectively.

When examined across subgroups, additional factors that were associated with a more significant DFS benefit with pembrolizumab was patients of the European Union (HR, 0.49; 95% CI, 0.32-0.74), present sarcomatoid features (HR, 0.56; 95% CI, 0.29-1.06), and grade 4 tumors (HR, 0.57; 95% CI, 0.37-0.87).

OS data remain immature and the median OS has not yet been reached in either arm. However, there is a trend toward improved survival with pembrolizumab (HR, 0.54; 95% CI, 0.30-0.96; 

 = .0164). Eighteen events (3.6%) have occurred in the pembrolizumab arm compared with 33 events (6.6%) in the placebo arm. The 1-year DFS rates were similar at 98.6% and 98.0% with pembrolizumab and placebo, respectively; at 2 years, these rates were 96.6% and 93.5%, respectively.

Safety findings showed that all-cause adverse events (AEs) occurred in 96.3% of patients on pembrolizumab and 91.1% of those on placebo; grade 3 to 5 AEs occurred in 32.4% and 17.7% of patients, respectively, and 20.7% and 2.0% of patients, respectively, had AEs led that led to treatment discontinuation. Two patients on pembrolizumab had AEs that led to death compared with 1 patient on placebo.

Serious all-cause AEs occurred in 20.5% of patients on pembrolizumab and 11.3% of patients on placebo; these AEs led to treatment discontinuation in 10.0% and 1% of patients, respectively. Treatment-related AEs (TRAEs) that were all-grade and grades 3 to 5 occurred in 79.1% and 18.9% of pembrolizumab-treated patients and 53.4% and 1.2% of placebo-treated patients, respectively. A total 17.6% of patients on pembrolizumab had AEs led to treatment discontinuation vs 0.6% on placebo. No TRAEs on either arm led to death.

Grade 3/4 AEs that occurred in more than 5% of patients on pembrolizumab were fatigue, diarrhea, rash, pruritis, hypothyroidism, hyperthyroidism, arthralgia, myalgia, and asthenia. A total 7.4% of patients on pembrolizumab received high-dose (≥40 mg/day) of systemic corticosteroids for immune-mediated AEs compared with 0.6% of those on placebo.

1. Choueiri T, Pembrolizumab (pembro) vs placebo as post nephrectomy adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): randomized, double-blind, phase 3 KEYNOTE-564 study. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Plenary session. https://bit.ly/392XAL7

2. FDA grants priority review to Merck’s supplemental biologics license application for KEYTRUDA (pembrolizumab) as adjuvant therapy in certain patients with renal cell carcinoma (RCC) following surgery. News release. Merck. August 10, 2021. Accessed September 14, 2021. https://bit.ly/3jEcyMt

“Although numbers of participants with certain disease risk features were small, the DFS benefit was consistent across subgroups,” said lead study author Toni K. Choueiri, MD.

Gina Mauro

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