ARASENS: the addition of darolutamide to ADT plus docetaxel significantly improves overall survival for patients with mHSPC

Androgen-deprivation therapy (ADT) is the standard-of-care (SOC) mainstay for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). In the last five years, clinical trials have demonstrated an increased overall survival (OS) with the addition of docetaxel in this patient population.1

Darolutomide is a highly potent and structurally distinct androgen receptor (AR) inhibitor with limited drug-drug interactions and minimal blood-brain barrier penetration that has been shown to improve OS for patients with non-metastatic, castration-resistant prostate cancer (CRPC).2 The Phase III ARASENS (NCT02799602) trial was designed to investigate whether the addition of darolutamide to ADT plus docetaxel could demonstrate an improved OS for patients with mHSPC, the results of which were presented at the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022.3

The international, double-blind trial randomized 1306 patients with mHSPC to receive darolutamide (n=651) or placebo (n=655) in combination with docetaxel plus ADT. The primary endpoint was OS and secondary endpoints included time to CRPC, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent systemic antineoplastic therapies. Safety was additionally assessed.

At the time of primary data cutoff, the risk of death was significantly decreased by 32.5% with darolutamide versus placebo (HR 0.68; 95% CI, 0.57 to 0.80; P<0.001). The OS benefit was shown to be consistent across prespecified subgroups. Darolutamide also demonstrated a significantly longer time to progression compared to placebo (HR, 0.792, 95% CI 0.660–0.950; P= 0.0058) and a benefit was shown in all other secondary endpoints.

Adverse events were similar between treatment arms, and incidences of most common adverse events (=10%) were highest during the overlapping docetaxel treatment period for both arms. Adverse events led to treatment discontinuation in 13.5% and 10.5% of patients in the darolutamide and placebo arm, respectively.

The results of the ARASENS trial demonstrates that the addition of darolutamide to ADT plus docetaxel for the early treatment of mHSPC markedly increases OS, additionally improving key secondary endpoints. Findings from ARASENS indicates this triplet therapy as a favorable new SOC option for mHSPC.


PROPEL: the addition of olaparib to abiraterone delays disease progression by 8 months in patients with mCRPC

Treatment options are limited for metastatic castration-resistant prostate cancer (mCRPC) and patients will often experience disease progression following initial treatment with the current standard of care (SOC), resulting in a poor 5-year survival rate.4 The PARP inhibitor (PARPi), olaparib, is currently approved for the treatment of patients with mCRPC who harbor homologous recombination repair (HRR) gene mutations following progression on either of the androgen receptor (AR) inhibitors, enzalutamide or abiraterone.5 However, preclinical data suggests the co-inhibition of PARP and AR induces synthetic lethality, regardless of HRR mutation status.6 Indeed, multiple models have demonstrated the requirement of PARP-1 for AR function, in addition to tumor cell growth and the initiation and maintenance of castration resistance.

Furthermore, it has been shown that AR aids in the expression and activity of HRR genes in prostate cancer.7 This generated the rationale for the Phase III PROpel (NCT03732820) clinical trial, investigating the addition of olaparib to abiraterone for patients with mCRPC, with or without (HRR) gene mutations.8 The interim analysis results of PROpel were presented at the American Society for Clinical Oncology (ASCO) Genitourinary Cancer Symposium 2022. The primary endpoint was radiographic progression-free survival (rPFS), with multiple secondary endpoints, including overall-survival (OS), time to first subsequent treatment (TTFS) and time to second progression or death (PFS2). The double-blind trial randomized a total of 796 patients to receive either olaparib plus abiraterone (n=399) or abiraterone plus placebo (n=397). 28% of patients harbored HRR mutations as detected by circulating tumor DNA (ctDNA).

PROpel met its primary objective at the interim analysis, with patients receiving olarparib plus abiraterone exhibiting a significantly improved rPFS of 8 months versus treatment with abiraterone monotherapy, regardless of HRR status (24.8 vs 16.6 months; HR 0.66, 95% CI 0.54–0.81; P<0.0001). The improvement was demonstrated across all subgroups in a predefined subgroup analysis, including in patients with HRR mutations (HR 0.54, 95% CI 0.36–0.79) and those without (HR 0.76, 95% CI 0.59–0.97).

Additionally, a trend was observed toward an improved OS with olaparib plus abiraterone (HR 0.86, 95% CI 0.66–1.12), which will continue to be assessed as a key secondary endpoint.

Time to subsequent treatment reinforced long-term benefits (HR 0.74, 95% CI 0.61–0.90), as well as time to second PFS or death (HR 0.69, 95% CI 0.51–0.94).

The most commonly reported grade 3 adverse event observed was anaemia in 15.1% versus 3.3% patients receiving olaparib plus abiraterone compared to abiraterone alone, respectively, and 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus abiraterone, respectively.

PROpel has demonstrated encouraging interim analysis results with the addition of olaparib to abiraterone, notably delaying disease progression by 8 months in patients with mCRPC, with ongoing OS results appearing favorable, presenting a potentially promising new first-line SOC option for this patient population, regardless of biomarker status.

TROPHY-U-01: sacituzumab govitecan plus pembrolizumab demonstrate encouraging results for patients with metastatic urothelial carcinoma

Survival outcomes for patients with metastatic urothelial carcinoma (mUC) are poor, and treatment options following disease progression on platinum-based chemotherapy and checkpoint inhibitors are limited, with CPIs demonstrating a 13–29% response rate.9 Trop-2 is an epithelial cell surface antigen that is commonly overexpressed in UC.10,11

The multicohort Phase II TROPHY-U-01 (NCT03547973) trial investigated sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate (ADC) coupled to SN-38 via a hydrolyzable linker, in combination with the anti-PD-1 checkpoint inhibitor, pembrolizumab, in patients with mUC who are CPI-naïve and have experienced disease progression following treatment with platinum-based chemotherapy (cohort 3).12 

ADCs can instigate immunogenic cell death and combining sacituzumab govitecan with an immune checkpoint blockade inhibitor may induce additive or synergistic activity, providing the rationale for this clinical trial. The interim analysis results of TROPHY-U-01 were presented at the American Society for Clinical Oncology (ASCO) Genitourinary Cancer (GU) Symposium 2022.

The primary outcome for cohort 3 of the TROPHY-U-01 trial was overall response rate (ORR) by blinded independent review; key secondary endpoints included clinical benefit rate (CBR), progression-free survival (PFS) and safety. 61 patients were enrolled, 41 of whom had received at least one dose of sacituzumab govitecan at data cut off. The investigator-assessed ORR was 34% (95% CI, 20.1–50.6; 1 complete response (CR); 13 partial responses (PR)) at a median follow-up of 5.8 months were observed. Patients demonstrated a CBR of 44% (95% CI, 28.5–60.3) and the 6-month PFS rate was 47%. 59% of patients experienced grade 3 adverse events and 2 patients discontinued treatment due to adverse events.

In conclusion, the TROPHY-U-01 trial demonstrated encouraging results and a manageable safety profile with the combination of sacituzumab govitecan and pembrolizumab in patients with mUC who had progressed on treatment with platinum-based chemotherapy, supporting continued investigation of the combination in this patient population.

Adjuvo: results do not support treatment with adjuvant mitotane for patients with adrenocortical carcinoma at low-intermediate risk of recurrence following surgery

Surgery is the backbone of adrenocortical carcinoma (ACC) treatment, however, due to the rarity of the disease, diagnosis is usually delayed, and approximately 40-70% of patients will experience relapse following surgery.13 The ESE-ENSAT guidelines indicate adjuvant therapy with mitotane for patients with ACC who are at high-risk of recurrence following radical surgery, although there is a lack of evidence derived from randomized control trials to support this indication. Furthermore, due to the absence of stratification in clinical studies of ACC, there is no recommendation for intermediate-low risk patients.14 The randomized controlled Adjuvo (NCT00777244) trial was designed to investigate whether treatment with adjuvant mitotane could prolong disease-free survival of patients with ACC at low-intermediate risk of recurrence following radical resection.15

The primary endpoint of the Adjuvo trial was recurrence-free survival (RFS) and secondary endpoints included overall survival (OS) and safety. Patients were randomized to receive mitotane or active surveillance. A total of 91 patients were enrolled, 45 received adjuvant mitotane and 47 were observed. Baseline characteristics were well balanced between the two arms. 8 patients receiving mitotane and 11 undergoing observation experienced disease relapse at a median follow-up of 48 months, with deaths of 2 and 5 patients in either arm, respectively. The difference in RFS and OS rates between the two arms was non-significant. Hazard ratio (HR) for recurrence was 1.321 (95% CI, 0.55-3.32; P = 0.54) and the HR for death was 2.171 (95% CI, 0.52-12.12; P = 0.29) in the observational arm.

Patients receiving mitotane versus active surveillance demonstrated a 5-year RFS rate of 79%, 75% (95% CI, 0.55-3.32, p = 0.52) and 5-year overall-survival rate of 95% and 86% (HR, 0.46; 95% CI, 0.08-1.92; P = 0.27), respectively.

Patients with ACC at low-intermediate risk of recurrence following surgery are a minority, with most patients at high-risk of relapse. The Adjuvo trial revealed patients at low-intermediate risk of relapse following surgery have a much better prognosis, with results demonstrating a lack of support for adjuvant treatment with mitotane in this patient population. Due to the lack of benefit to recurrence-free survival, patients with low-intermediate risk of relapse following surgery can safely avoid treatment with mitotane and the associated toxicities.

BAYOU: patients with advanced urothelial carcinoma who harbor HRR mutations show promising results from treatment with durvalumab plus olaparib

Mutations in DNA damage and repair genes, such as in homologous recombination repair (HRR) genes, are common in patients with urothelial carcinoma (UC). Tumor cells with HRR mutations exhibit sensitivity to PARP inhibition and data suggests that patients who harbor these mutations demonstrate a better response to immunotherapy (IO).16 The PD-1 inhibitor, durvalumab, is approved for treatment of patients with locally advanced or metastatic UC following progression on platinum-based chemotherapy. However, prognosis remains poor for patients with advanced or metastatic UC, particularly for those who are not suitable for treatment with platinum-based chemotherapy. The Phase II BAYOU (NCT03459846) clinical trial is investigating first-line durvalumab plus the PARP inhibitor, olaparib, versus durvalumab alone for the treatment of patients with unresectable stage IV UC who are ineligible for platinum-based chemotherapy.16

The primary endpoint of the BAYOU trial was progression-free survival (PFS) in the intention-to-treat (ITT) population. Secondary endpoints included overall-survival (OS) in the ITT population, overall response rate (ORR) and PFS in the subset of patients with HRR mutations. Patients were randomized 1:1 to receive either durvalumab plus olaparib or durvalumab monotherapy and stratified according to centrally-determined HRR status (mutant versus wild-type) and Bajorin risk index.

A total of 154 patients were randomized to receive either durvalumab plus olaparib (n=78) or durvalumab plus placebo (n=76). 22% and 18% of patients respectively had mutations in HRR genes in the combination and monotherapy group. At data cut-off, the primary endpoint was not met, showing no significant difference in median PFS between durvalumab plus olaparib (4.2 months) and durvalumab alone (3.5 months) in the ITT population (HR 0.94, 95% CI 0.64-1.39). However, in the subset of patients with HRR mutations, median PFS was 5.6 months versus 1.8 months for patients receiving olaparib plus durvalumab versus durvalumab. Median OS (95%) was 10.2 months (7.0–13.9) in the monotherapy group and 10.7 months (7.2-17.3) in the combination group. 18% and 9% of patients in the combination and monotherapy group experienced grade 3-4 adverse events, respectively.

The combination of durvalumab and olaparib did not meet its primary endpoint by prolonging PFS compared to durvalumab alone in patients with advanced UC. However, the results of patients with advanced UC who harbor HRR mutations warrants further investigation for this IO combination in this subgroup.


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Written by Esther Drain