Lisa Astor 

Findings from the phase 2 ARNEO trial (NCT03080116) showed that adding apalutamide (Erleada) to the hormone therapy degarelix (Firmagon) in the neoadjuvant setting increased the likelihood of achieving minimal residual disease (MRD) negativity vs degarelix alone in patients with high-risk prostate cancer after radical prostatectomy.

MRD levels below 0.25 mL, the primary end point of the trial, was achieved in 38% of patients in the apalutamide combination arm (n = 45) compared with 9% in the degarelix monotherapy arm (n = 44; risk ratio, 4.2; 

 = .002). The residual cancer burden was a median of 0.48 mL with the doublet and 1.7 mL with the single agent (

“Patients [with high-risk prostate cancer] treated with degarelix plus apalutamide achieved a significantly better tumor response compared [with] the patients treated with degarelix plus matching placebo,” said Steven Joniau, MD, PhD, a consulting urologist and assistant professor in the Department of Urology at University Hospitals Leuven in Belgium, when presenting findings from the ARNEO trial during the European Association of Urology Congress 2022.

Downstaging was more common following treatment with apalutamide and degarelix than with degarelix and placebo. In the combination arm, downstaging to pT2 occurred in 51% of patients compared with 27% in the monotherapy arm (

= .03), and downstaging to pT3a occurred in 27% and 39%, respectively.

The probability of biochemical recurrence was significantly reduced in patients who achieved pathologic complete response to treatment and had MRD negativity compared with those who had MRD positivity. “Deep pathological response was correlated with less or almost no risk of biochemical progression,” Joniau said.

Historically, clinical trials have not shown a survival benefit for neoadjuvant treatment prior to radical prostatectomy despite demonstration of pathological response, but Joniau noted that these studies explored the use of first-generation antiandrogens in men with low- and intermediate-risk prostate cancer. However, one retrospective analysis did show a survival benefit for neoadjuvant hormonal therapy in patients with high-risk prostate cancer. The analysis showed that the risk of prostate cancer–related death was decreased by 50% with neoadjuvant treatment (

 = .0014), but it was suggested that it could have been due in part to the use of radiotherapy after surgery.

The ARNEO study enrolled patients with high-risk nonmetastatic prostate cancer who had a prostate-specific antigen (PSA) level higher than 20 ng/mL, a Gleason score between 8 and 10, and/or 2 to 3 intermediate risk factors. Statistical analysis required at least 84 patients to be enrolled. Patients were randomly assigned to receive either neoadjuvant degarelix and apalutamide or degarelix and placebo for 3 months prior to surgery. Blinded prostate-specific membrane antigen (PSMA) PET/MRI scans were conducted before and after treatment. The primary end point was MRD rate, and secondary end points included PSA kinetics, toxicity, quality of life, and biomarkers for pathological response.

At baseline in the combination arm, the median PSA level was 12.6 ng/mL, and most patients had cT3a disease (40%) and an International Society of Urological Pathology (ISUP) grade of 5 (43%). Comparatively in the degarelix monotherapy arm, the median PSA level was 11.2 ng/mL, and most patients had cT3a disease (46%) and ISUP grade 4 disease (39%).

 < .0001) and PSMA maximum standard uptake value (

 < .0001) after neoadjuvant therapy were correlated with cancer volume at final pathology and pathological response. PTEN loss was considered a negative predictor for MRD, as patients with PTEN loss at baseline were less likely to achieve MRD (11% vs 43% with PTEN; 

 = .002). Joniau concluded that this study was a solid foundation for ongoing and planned phase 3 trials in this setting.

1. Devos G, Tosco L, Baldewijns M, et al. ARNEO: a randomized phase II trial of neoadjuvant degarelix with or without apalutamide prior to radical prostatectomy for high-risk prostate cancer. Presented at: European Association of Urology Congress 2022; July 1-4, 2022; Amsterdam, Netherlands.

2. Tosco L, Laenen A, Briganti A, et al. The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(4):407-412. doi:10.1038/pcan.2017.29

Articles

Adding apalutamide to the hormone therapy degarelix in the neoadjuvant setting increased the likelihood of achieving minimal residual disease negativity in patients with high-risk prostate cancer after radical prostatectomy.

Neoadjuvant combo boosts MRD negativity rates in high-risk prostate cancer

Findings from the phase 2 QUEST trial presented during the 2022 AUA Annual meeting showed promising early activity with the PARP inhibitor niraparib (Zejula) plus the androgen receptor pathway inhibitor abiraterone acetate (Zytiga) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations who had progressed on prior treatment with an androgen receptor (AR)–targeted therapy.

Treatment with the triplet regimen led to a composite response in more than half of all patients (56.5%; 90% CI, 37.5%-74.2%).

The study authors, led by Kim N. Chi, MD, a senior research scientist at Vancouver Prostate Centre, a medical oncologist at BC Cancer in Vancouver, and a professor in the Department of Medicine at the University of British Columbia, explained in their paper that they expected that targeting both the PARP and AR oncogenic pathway may enhance efficacy in mCRPC, and the QUEST trial is part of a larger program to investigate the combination.

The QUEST trial began in March 2018 and enrolled adult patients with mCRPC and HRR gene alterations who received 1 line of therapy with a next-generation AR-targeted agent and an ECOG performance status of 0 or 1. Patients were divided between 3 cohorts based on their HRR gene alterations: biallelic 

alterations (n = 9), and other monoallelic alterations (n = 6). All participants received all-oral 200 mg niraparib plus 1000 mg abiraterone acetate and 10 mg prednisone daily.

Composite response rate (CRR) and the severity of adverse events (AEs) were the primary end points of the trial and secondary end points included objective response rate (ORR), circulating tumor cell (CTC) response rate, and radiographic progression-free survival (rPFS). CRR was defined as the quantity of patients with an objective response, overall CTC response, and/or prostate-specific antigen (PSA) decline of at least 50% (PSA50). CTC response was defined as CTC0 response at 8 weeks or CTC conversation.

A total of 24 patients were included in the safety population with a median age of 73 years (range, 58-88). Most patients were White (87.5%) and the remainder were Black or African American (12.5%). A large majority of patients (95.8%)were not Hispanic or Latino. Patients had an ECOG performance status of 0 (58.3%) or 1 (41.7%), and Gleason scores ranged from less than 7 (8.3%) to 8 or higher (62.5%), and scores were unknown in 8.3%. Disease was observed in the bone in 91.7% of patients or was bone only in 54.2%, visceral disease was reported in 4.2%, lymph node disease in 37.5%, or in other sites in 8.3%. Additionally, 42% had soft tissue or nodal metastases.

In terms of prior treatments, 7 patients (29.2%) had received prior taxanes, and all patients had received prior AR-targeted therapy, prostate cancer–related radiotherapy, and surgery.

At a median follow-up of 18 patients, 8 patients were still receiving treatment and the median duration of treatment with the triplet regimen was 10.3 months (range, 0.7-22.0).

The intention-to-treat (ITT) efficacy population included 23 patients since 1 patient was HRR negative. Among these patients, the ORR was 21.7% (90% CI, 12.0%-45.1%), the overall CTC response rate was 26.1% (90% CI, 12.0%-45.1%), and the PSA50 response rate was 30.4% (90% CI, 15.2%-49.6%).

The median duration of response was 4.7 months (range, 3.7-8.2). The median rPFS was 11.0 months (90% CI, 9.7-not estimable). At 3 months, the rPFS rate was 85.1% (95% CI, 70.8%-100.0%), 74.1% (95% CI, 56.8%-96.7%) at 6 months, 74.1% (95% CI, 56.8%-96.7%) at 9 months, and 46.7% (95% CI, 25.3%-86.1%) at 12 months.

Among 10 patients with measurable disease, 50% had a partial response as their best overall response, 20% had stable disease, and 30% had progressive disease. Six of 10 patients had a maximum reduction in target lesions of at least 30%.

At 8 weeks, CTC0 response was achieved in 17.4% (90% CI, 6.2%-35.5%) and the CTC conversion rate was 21.7% (90% CI, 9.0%-40.4%).

The most common treatment-emergent AEs (TEAEs) observed with the combination of niraparib, abiraterone acetate, and prednisone were anemia, fatigue, constipation, thrombocytopenia, nausea, vomiting, and decreased appetite. Frequent grade 3 or higher TEAEs included anemia (41.7%), thrombocytopenia (20.8%), fatigue (16.7%), and neutropenia (12.5%). Serious drug-related events were reported in 3 patients due to lower gastrointestinal hemorrhage, asthenia and noncardiac chest pain, and anemia in 1 patient each. No deaths were observed in the study due to AEs.

Dose interruption/reduction was required in 58.3% of patients, most commonly due to anemia, thrombocytopenia, and neutropenia. Treatment discontinuation due to TEAEs was reported in 8.3% of patients.

“These findings are consistent with those of the GALAHAD [NCT02854436] and BEDIVERE [NCT02924766] studies and the recently reported outcomes in the phase 3 MAGNITUDE study [NCT03748641], supporting the continued development of the combination of polyadenosine diphosphate–ribose polymerase (PARP) and AR inhibitors in patients with mCRPC and HRR gene alterations,” Chi et al wrote in their poster.

1. Chi K, Fleshner N, Chiuri VE, et al. Niraparib with abiraterone acetate and prednisone for metastatic castration-resistant prostate cancer: results from the phase 2 QUEST study. Presented at: 2022 AUA Annual Meeting; New Orleans, LA; May 13-16, 2022. Abstract MP27-17.

Videos

A regimen combining the PARP inhibitor and the androgen receptor pathway inhibitor plus prednisone showed promise in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had progressed on prior treatment with an androgen receptor–targeted therapy.

Niraparib/abiraterone regimen shows early efficacy signals in metastatic prostate cancer

Updated phase 2 data presented at the 2021 ASCO Annual Meeting showed that the HIF-2α inhibitor belzutifan (MK-6482) continued to induce strong responses as a first-line treatment for patients with Von-Hippel Lindau (VHL)–associated renal cell carcinoma (RCC).

The investigational agent also showed activity against other VHL-associated neoplasms, according to lead study author Ramaprasad Srinivasan, MD, PhD, and coinvestigators.

“This update continues to demonstrate the activity of belzutifan in patients with VHL-associated renal and non-renal tumors accompanied by an acceptable safety profile,” said Srinivasan, head of the Molecular Cancer Therapeutics Section, Center for Cancer Research, National Cancer Institute.

Recently, the FDA granted belzutifan a priority review for the treatment of patients with VHL disease–associated RCC who do not require immediate surgery based on earlier results of this study.2

The open-label, single-arm study enrolled 61 patients who were diagnosed with VHL disease based on germline alteration who had at least 1 measurable RCC tumor, had not received any prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of 0 or 1. Patients were treated with 120 mg oral daily belzutifan as a potential systemic treatment for VHL-associated RCC and other VHL neoplasms.

Objective response rate (ORR) in RCC tumors per RECIST criteria by independent review committee was the primary end point and secondary end points included ORR in non-RCC neoplasms, duration of response (DOR), and safety.

The median age was 41 years (range, 19-66) at baseline and the majority of patients were male (52.5%) and had an ECOG performance status of 0 (82.0%). Pancreatic lesions were also reported in all patients, 36.1% of which were neuroendocrine; central nervous system (CNS) hemangioblastomas were reported in 82.0% of patients and retinal lesions in 26.2%.

As of data cutoff, a median of 21.8 months (range, 20.2-30.1) after enrollment, 88.5% of patients were still receiving treatment.

Responses in target RCC lesions were observed in 30 patients (49.2%; 95% CI, 36.1%-62.3%) of patients by independent review committee; all responses were partial responses (PRs), and another 4 patients had unconfirmed PRs. Stable disease was reported in 49.2% of patients and 1 patient was not evaluable. Ninety-two percent of patients had a decrease in target RCC lesion size.

The median time to response was 8.2 months (range, 2.7-19.1) and the duration of response was not reached (range, 2.8+ to 22.3+). Progression-free survival rate at 12 months was 98.3% and 96.5% at 24 months, and the median has not yet been reached.

In pancreatic lesions, responses were reported in 77.0% (95% CI, 64.5%-86.8%), with complete responses (CRs) in 9.8% and PRs in 67.2%. Among pancreatic neuroendocrine tumors, the ORR was 90.9% (95% CI, 70.8%-98.9%) with CRs in 13.6% and PRs in 77.3%. The ORR was 30.0% (95% CI, 17.9%-44.6%) in CNS hemangioblastomas with CRs in 6.0% and PRs in 24.0%.

Srinivasan noted that retinal hemangioblastomas were not amenable to classic response evaluation with RECIST criteria. Sixty-nine percent of retinal hemangioblastomas were improved and 31% were stable as best response.

All patients reported a treatment-related adverse event (TRAE) of any grade, grade 3 events were observed in 32.8% and grade 4 or 5 events in 14.8%. TRAEs led to discontinuation in 1.6% of patients and an adverse event led to death in 1 patient, but the event was not treatment related.

The most common AEs of any grade were anemia (90.2%), fatigue (65.6%), headache (41.0%), dizziness (39.3%), and nausea (34.4%). Most of the events were grade 1 or 2, but common grade 3 events were anemia (8.2%) and hypertension (8.2%). Srinivasan said that anemia was a predicted on-target effect of HIF-2–dependent downregulation of erythropoietin.

1. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase 2 study of belzutifan (MK-6482), an oral hypoxia-inducible factor 2α (HIF-2α) inhibitor, for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC). 

2021;39(suppl 15):4555. doi:10.1200/JCO.2021.39.15_suppl.4555

2. Merck Receives Priority Review from FDA for New Drug Application for HIF-2α Inhibitor Belzutifan (MK-6482). News release. Merck. March 16, 2021. Accessed June 7, 2021. https://bit.ly/38NLYM2

The HIF-2α inhibitor continued to induce strong responses in patients with Von-Hippel Lindau (VHL)–associated renal cell carcinoma and other VHL-associated neoplasms.

Update sustains strong activity with belzutifan in VHL-associated kidney cancer

Results from the confirmatory phase 3 EV-301 trial shared during the 2021 Genitourinary (GU) Cancers Symposium showed that the antibody-drug conjugate enfortumab vedotin (Padcev) reduced the risk of death by 30% versus chemotherapy in patients with heavily pretreated locally advanced or metastatic urothelial carcinoma.

Patients enrolled in the trial had previously received platinum-based chemotherapy and a PD-1/L1 inhibitor. The findings, which were simultaneously published in the 

, showed that enfortumab vedotin improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) versus chemotherapy in this patient population.

“Enfortumab vedotin is the first drug beyond chemotherapy and immunotherapy to show a significant survival advantage in previously treated advanced urothelial cancer,” said Thomas Powles, MBBS, MRCP, MD, in a presentation during the GU Cancers Symposium. “This is a big step in the right direction for patients with advanced urothelial cancer, where treatment options remain quite limited.”

The Nectin-4–directed antibody-drug conjugate was granted an accelerated approval by the FDA in December 2019 for the treatment of adult patients with locally advanced or urothelial cancer who have previously received a PD-1/ L1 inhibitor and platinum-containing chemotherapy.

 Accelerated approval was granted because treatment options are limited once urothelial cancer has progressed on both chemotherapy and immunotherapy. Data from the phase 2 EV-201 trial supported the approval.

The open-label, randomized EV-301 trial (NCT03474107) served as a confirmatory trial for the benefit of enfortumab vedotin over chemotherapy in this setting following the FDA approval.

A total of 608 patients with histologically or cytologically confirmed urothelial cancer, including patients with squamous differentiation or mixed cell types, were enrolled in the study and randomized 1:1 with stratification to either the enfortumab vedotin (n = 301) arm or the chemotherapy arm (n = 307). Eligible patients had radiographic progression or relapsed during or after immune checkpoint inhibition for the treatment of advanced urothelial cancer and had received prior platinum-containing chemotherapy; patients also had an ECOG performance status of 0 or 1. Stratification variables included ECOG performance status (0 or 1), region of the world, and the presence or absence of liver metastasis.

In the investigational arm, enfortumab vedotin was administered at 1.25 mg/kg on days 1, 8, and 15 of every 28-day cycle. Chemotherapy in the control arm consisted of docetaxel at 75 mg/m2, paclitaxel at 175 mg/m2, or vinflunine 320 mg/m2 each given on day 1 of every 21-day cycle.

OS was the primary end point of the study and secondary end points included PFS, ORR, disease control rate (DCR)—all assessed by the investigator per RECIST v1.1 criteria—and safety.

With enrollment of approximately 600 patients, the study had 85% power to detect a statistically significant difference in efficacy at an overall 1-sided 0.025 type I error rate with a hazard ratio of 0.75.

The trial was planned to have 2 analyses, an interim one at 285 deaths (65%) and a final analysis at 439. For the interim analysis, OS was tested with a 1-sided difference of 0.00679.

Powles, a professor of genitourinary oncology, director of the Barts Cancer Center, and lead for Solid Tumor Research at the Barts Cancer Institute, in London, United Kingdom, explained that as interim analysis was positive for survival this became the primary analysis.

Baseline characteristics were balanced between the 2 arms. The median age was 68 years and more than three-fourths of patients were male. Only 14% of patients were from the United States, 60% had an ECOG performance status of 1, two-thirds had a Bellmunt risk score of 0 or 1, 31% had liver metastases, and 87% had 1 or 2 prior lines of therapy. In the enfortumab vedotin arm, 20% responded to prior immune checkpoint inhibition and 16% responded in the chemotherapy arm.

As of data cutoff, 81% of patients had discontinued treatment in the enfortumab vedotin arm versus 93% in the chemotherapy arm, which was due to progressive disease in 59% of patients in both arms. At a median follow-up of 11.1 months, the median treatment exposure was 5.0 months (range, 0.5-19.4) in the enfortumab vedotin and 3.5 months (range, 0.2-15.0) in the chemotherapy arm.

The median OS with enfortumab vedotin was 12.88 months (95% CI, 10.58-15.21) versus 8.97 months (95% CI, 8.05-10.74) with chemotherapy, which translated to a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.56-0.89; 

= .00142). Powles commented that the Kaplain-Meier curves for OS “go apart and stay apart, and the data look impressive in my opinion.”

Subgroup analyses for OS favored the enfortumab vedotin arm for all groups excepts female patients (HR, 1.17), although Powles noted that some of the subgroups were too small to draw conclusions.

Median PFS with enfortumab vedotin was 5.55 months (95% CI, 5.32-5.82) versus 3.71 months (95% CI, 3.52-3.94) with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; 

Confirmed ORR in the enfortumab vedotin arm was 40.6% (95% CI, 34.9%-46.5%), which included complete responses in 4.9%, and the DCR was 71.9% (95% CI, 66.3%-77.0%). In the chemotherapy arm, the ORR was 17.9% (95% CI, 13.7%-22.8%) with complete responses in 2.7%, and a DCR of 53.4% (95% CI, 47.5%-59.2%; 

Treatment-related adverse event (TRAE) rates were similar between the 2 arms, with any-TRAE rates of 94% in the investigational arm and 92% in the control arm, and grade ≥3 TRAE rates of 51% and 50%, respectively. Serious TRAEs were reported in 23% of patients in each arm and TRAEs led to treatment discontinuation in 14% of patients in the enfortumab vedotin arm and 11% in the chemotherapy arm.

Powles highlighted that the rate of grade ≥3 maculopapular rash was increased in the enfortumab vedotin arm (7% vs 0%), whereas rates of grade ≥3 neutrophil count decrease (6% vs 13%), white blood cell count decrease (1% vs 7%), and febrile neutropenia (1% vs 6%) were all higher in the chemotherapy arm.

TRAEs of special interest in the enfortumab vedotin arm included skin reactions of rash (all grade, 44%; grade ≥3, 15%) and severe cutaneous adverse reactions (all grade, 20%; grade ≥3, 5%), peripheral neuropathy in terms of sensory events (all grade, 44%; grade ≥3, 4%) and motor events (all grade, 7%; grade ≥3, 2%), and hyperglycemia (all grade, 6%; grade ≥3, 4%). The majority of TRAEs of special interest were mild to moderate in severity.

1. Powles T, Rosenberg JE, Sonpavde G, et al. Primary results of EV-301: A phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial carcinoma. 

2021;39(suppl 6):393. doi:10.1200/JCO.2021.39.6_suppl.393

2. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. Published online February 12, 2021. 

3. FDA approves new type of therapy to treat advanced urothelial cancer. FDA website. December 18, 2019. Accessed February 12, 2021. https://bit.ly/3agPr77

The antibody-drug conjugate was previously granted an accelerated approval by the FDA in this setting based on results from the phase 2 EV-201 trial.

Lisa Astor

Articles

Neoadjuvant combo boosts MRD negativity rates in high-risk prostate cancer

Niraparib/abiraterone regimen shows early efficacy signals in metastatic prostate cancer

Update sustains strong activity with belzutifan in VHL-associated kidney cancer

Enfortumab Vedotin extends overall survival in phase 3 confirmatory urothelial carcinoma trial