Benjamin Saylor

A molecular signature has been identified that can characterize long-term responders from treatment with apalutamide (Erleada) and androgen deprivation therapy (ADT) in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), according to findings, presented at the 2021 Genitourinary Cancers Symposium.

Data were derived from an exploratory analysis of patients from the phase 3 randomized, placebo-controlled SPARTAN trial (NCT01946204). At the final analysis of SPARTAN, treatment with apalutamide plus ADT increased median overall survival by 14 months versus placebo plus ADT in patients with nmCRPC.2 Based on initial data from the SPARTAN trial, the FDA approved apalutamide in 2018 for use in this setting.

For the current study, investigators characterized patients in the biomarker population of SPARTAN as either long-term responders (LTRs) or early progressors (EPs). Patients from the apalutamide plus ADT and placebo plus ADT groups were placed in quartiles based on the number and timing of metastatic events. Patients without progression or who reached a metastatic event after the third quartile were considered LTRs, whereas patients who had a metastatic event in the first quartile were considered EPs.

“Because patients in the placebo group had previously progressed on androgen deprivation therapy alone, our analysis focused only on the long-term responder population treated with apalutamide plus androgen-deprivation therapy,” said study investigator Felix Y. Feng, MD, professor of radiation oncology, urology, and medicine at the University of California, San Francisco and director of the Benioff Initiative for Prostate Cancer Research at Helen Diller Family Comprehensive Cancer Center.

The SPARTAN biomarker population comprised 233 tumors collected at radical prostatectomy or during diagnostic biopsies. “Gene expression profiling was used to identify molecular subtypes within the cohort, based on a selected number of predefined signatures representing distinct biological pathways or processes relevant in prostate cancer,” Feng said.

test method was used to analyze differential expressions in the LTR and EP groups. Signatures that showed nominal statistical significance were identified. In parallel, a Cox proportional hazards model was applied to the entire biomarker population to determine whether these signatures were associated with metastasis-free survival (MFS). The investigators then looked at signatures that were associated with response to treatment by both analyses. Signatures that were both differentially expressed in LTRs versus EPs and had a treatment-specific impact on clinical outcome were identified as predictive biomarkers of response to treatment, Feng said.

“Among patients treated with apalutamide, molecular signatures indicative of increased immune activity, decreased vascularization, or decreased proliferative capacity at baseline were each independently associated with long-term response. None of these signatures was associated with long-term response to placebo,” Feng reported.

In the placebo group, increased hormonal independence and metastatic capacity at baseline were associated with early progression.

Feng reported that signatures associated with long-term response to apalutamide plus ADT were also associated with increased MFS by Cox regression.

“Specifically, signatures of T cell proliferation and T cell stimulation at baseline were elevated in patients with long term response,” Feng said.

The investigators also found that patients with basal tumors with higher levels of T cell proliferation appeared to derive a similar benefit from apalutamide plus ADT compared with patients with luminal tumors.

1. Feng FY, Aguilar-Bonavides C, Lucas J, et al. Molecular determinants associated with long-term response to apalutamide (APA) in nonmetastatic castration-resistant prostate cancer (nmCRPC). 

. 2021;39(suppl 6):8. doi: 10.1200/JCO.2021.39.6_suppl.8

2. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer. 

2021;79(1):150-158. doi:10.1016/j.eururo.2020.08.011

Articles

A molecular signature has been identified that can characterize long-term responders from treatment with apalutamide and androgen deprivation therapy in patients with nonmetastatic castration-resistant prostate cancer, according to findings, presented at the 2021 Genitourinary Cancers Symposium.

Long-Term Responders of Apalutamide Identified With Molecular Signature in nmCRPC

Apalutamide (Erleada) in combination with androgen deprivation therapy (ADT) led to a reduction in the risk of death of 35% in comparison with ADT alone for patients with metastatic castration-sensitive prostate cancer (mCSPC) in a final analysis of the phase 3 TITAN trial.

The findings were presented at the 2021 Genitourinary Cancers Symposium by investigator Kim N. Chi, MD, chief medical officer and vice president of BC Cancer, Vancouver, Canada.

The randomized, double-blind, placebo-controlled TITAN trial (NCT02489318) included 1052 patients with mCSPC who were randomized 1:1 to receive apalutamide plus ADT or placebo plus ADT. Dual primary end points were radiographic progression-free survival (rPFS) and overall survival (OS).

Findings from the primary analysis of the trial were published in 2019.2 At a median follow-up of 22.7 months, both rPFS and OS reached statistical significance, according to Chi. The 2-year OS rates at the primary analysis was 82.4% in the apalutamide arm versus 73.5% in the control arm, translating to a 33% reduction in the risk of death (HR, 0.67; 

 = .005). Based on the primary TITAN analysis, the FDA approved apalutamide in September 2019 for the treatment of patients with mCSPC.

The primary TITAN analysis marked the final analysis for rPFS and first interim analysis for OS. Upon recommendation of the independent data monitoring committee, the trial was unblinded, and 39.5% of patients in the placebo group who had not progressed went on to receive open-label apalutamide.

Final analysis of the TITAN trial occurred at a median follow-up of 44.0 months. A total of 405 OS events had occurred. The median duration of treatment in the apalutamide plus ADT, crossover apalutamide plus ADT, and placebo plus ADT groups was 39.3 months, 20.2 months, and 15.4 months, respectively.

At the long-term follow-up, treatment with apalutamide plus ADT reduced the ­risk of death by 35% (HR, 0.65; 95% CI, 0.53-0.79; 

<.0001). After adjusting for crossover using a preplanned sensitivity analysis, investigators found a 48% reduction in the risk of death (HR, 0.52; 95% CI, 0.42-0.64; 

The treatment effect on OS was found to favor apalutamide plus ADT across all prespecified subgroups except for patients who had received prior docetaxel. “However, this subgroup comprised only 10% of patients, and among them, there have been relatively few events. A post hoc interaction analysis between treatment and prior use of docetaxel showed no significant interaction,” Chi noted.

Health-related quality of life (HRQOL) was measured using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score. Chi reported that HRQOL was maintained in the treatment group, with no difference between the treatment and placebo groups.

The safety profile of apalutamide plus ADT was found to be consistent with previous reports, according to Chi.

“Importantly, cumulative incidence of any-grade treatment-emergent falls, fractures, and fatigue was similar between groups. The cumulative incidence of grade 3/4 treatment-emergent adverse events and serious adverse events were also similar between groups. As expected, the incidence of any-grade rash was higher in the apalutamide group than in the placebo group, but reached a plateau after about 6 months,” Chi said.

1. Chi KN, Chowdhury S, Bjartell A, et al. Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT). 

. 2021;39(suppl 6):11. doi: 10.1200/JCO.2021.39.6_suppl.11

2. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. 

2019;381(1):13-24. doi:10.1056/NEJMoa1903307

Apalutamide in combination with androgen deprivation therapy led to a reduction in the risk of death of 35% in comparison with ADT alone for patients with metastatic castration-sensitive prostate cancer  in a final analysis of the phase 3 TITAN trial.

Apalutamide With ADT Maintains OS Benefit in mCSPC

In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), crossover from the placebo arm to the darolutamide (Nubeqa) treatment arm appeared have minimal impact on the overall survival (OS) benefit observed with the androgen receptor inhibitor in the pivotal phase 3 ARAMIS trial, according to findings from an analysis of the trial shared during the 2021 Genitourinary Cancers Symposium.

Darolutamide was approved by the FDA for the treatment of nmCRPC in July of 2019 based on findings from the ARAMIS trial (NCT02200614).

Presenting the findings at the virtual meeting, Neal D. Shore, MD, explained that in September 2018, the primary analysis of the ARAMIS trial found that darolutamide was associated with a statistically significant improvement in metastasis-free survival (MFS; the study’s primary end point) with a median MFS of 40.4 months versus 18.4 months with placebo (HR, 0.41; 

 The study was unblinded at the primary analysis, and 170 of 554 patients in the placebo arm went on to receive treatment with darolutamide.

The investigators performed 4 sensitivity analyses. Two of the analyses, rank-preserving structural failure time (RPSFT) and iterative parameter estimation (IPE), mimicked the Kaplan-Meier curve that would have been observed if the placebo-to-darolutamide switch had not occurred, according to Shore. The other analyses consisted of censoring at crossover and inverse probability of censoring weighting (IPCW).

“RPSFT and IPE are considered more reliable than the 2 censoring methods, which ignore survival duration after crossover and, in the case of IPCW, depend on the selection of baseline characteristics for inclusion in the model,” said Shore, medical director at Carolina Urologic Research Center in Myrtle Beach, South Carolina.

At the final analysis for both the double-blind and open-label periods, darolutamide was found to have significantly improved OS compared with placebo (HR, 0.69; 95% CI: 053-0.88, 

 Regarding the sensitivity analyses, Shore said they “showed the crossover likely had only a small dilutive effect on the OS results.”

Additionally, the safety profile of the treatment remained favorable at the final analysis, with no unexpected findings in the crossover group. Rates of adverse events were lower in the crossover group due to that group’s shorter exposure to darolutamide, Shore said.

Shore noted, “The interpretation of the sensitivity analyses is limited by the short duration of darolutamide treatment in the crossover group and by the potential bias in patient selection, as not all patients in the placebo arm received darolutamide on unblinding.

“However, the consistency of findings between the final overall survival analysis and the sensitivity analyses indicates that crossover from placebo to darolutamide has minimal impact on the overall survival benefit of darolutamide over placebo. These findings indicate that darolutamide is an effective and well-tolerated androgen receptor inhibitor as an early treatment option for patients with nonmetastatic castration-resistant prostate cancer,” Shore concluded.

1. Shore ND, Fizazi K, Tammela T, et al. Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial. 

 39, 2021 (suppl 6; abstr 240). doi: 10.1200/JCO.2021.39.6_suppl.240

2. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in nonmetastatic, castration-resistance prostate cancer. 

 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

3. Fizazi K, Shore N, Tammela TL, et al. Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide. 

 2020;383(11):1040-1049. doi:10.1056/NEJMoa2001342

In patients with nonmetastatic castration-resistant prostate cancer (nmCRPC), crossover from placebo to darolutamide (Nubeqa) appeared have minimal impact on the overall survival (OS) benefit observed with the androgen receptor inhibitor in the pivotal phase 3 ARAMIS trial.

In ARAMIS Trial, Crossover Has Minimal Impact on Darolutamide OS Benefit

The co-primary end points of overall survival in patients with metastatic urothelial cancer (UC) were not met in the phase 3 DANUBE trial of durvalumab in combination with tremelimumab and durvalumab (Imfinzi) monotherapy, according to results presented at the 2020 ESMO Virtual Congress.

Neither monotherapy with durvalumab (Imfinzi) or combination treatment with durvalumab plus tremelimumab met co-primary end points of overall survival versus chemotherapy for the treatment of metastatic urothelial cancer (UC).

However, secondary analyses suggested that tremelimumab bolstered the anti-tumor activity of durvalumab, particularly in patients whose tumors had high PD-L1 expression.

In introducing the DANUBE study, investigator Thomas Powles, MBBS, MRCP, MD, explained that although platinum-based chemotherapy yields initial high responses as first-line treatment for metastatic urothelial cancer, “patients relapse, and long-term, durable remissions are rare.

“Both atezolizumab [Tecentriq] and pembrolizumab [Keytruda] are approved in the cisplatin-ineligible, PD-L1-positive population in this frontline space. Their approval is based off 2 single-arm trials with relatively modest numbers.

 We don't currently have any mature, randomized overall survival data in this setting,” added Powles, professor of genitourinary oncology, director of Barts Cancer Centre, Queen Mary University of London, United Kingdom.

Durvalumab is approved by the FDA for the treatment of platinum-refractory, metastatic UC. Previous research has indicated that tremelimumab alone and the combination of durvalumab plus tremelimumab shows activity in platinum-refractory, metastatic UC regardless of PD-L1 expression.

The DANUBE trial evaluated durvalumab, with or without tremelimumab, vs platinum-based chemotherapy, as first-line treatment for metastatic UC (NCT02516241). The study included 1032 patients with untreated, unresectable, locally advanced, or metastatic UC.

Patients were randomized 1:1:1 to receive 1500 mg durvalumab IV once monthly until progression (n = 346); 1500 mg durvalumab IV once monthly until progression plus 75 mg tremelimumab once monthly for up to 4 doses (n = 342); and a standard-of-care chemotherapy regimen of gemcitabine plus cisplatin or carboplatin up to 6 cycles (n = 344). Randomization was stratified by cisplatin eligibility, PD-L1 status (high or low), and presence or absence of liver and/or lung metastases.

Baseline characteristics such as age, region, and pure transitional cell carcinoma were generally well balanced among the treatment groups.

Co-primary end points consisted of overall survival (OS) for durvaluamb vs chemotherapy in patients with high PD-L1 expression and OS for durvalumab plus tremelimumab vs chemotherapy in the intention-to-treat (ITT) population.

The minimum follow-up time was 34 months, and median follow-up for survival was 41.2 months for all patients.

Median OS for patients in the durvalumab-only group was 14.4 months vs 12.1 months for the chemotherapy group (HR, 0.89; 95% CI, 0.71-1.11) In the durvalumab plus tremelimumab cohort. Median OS was 15.1 months vs 12.1 months for the chemotherapy group (HR, 0.85; 95% CI, 0.72-1.02).

In regards to anti-tumor activity, median duration of response in the ITT population for patients in the durvalumab-only, durvalumab plus tremelimumab, and chemotherapy groups was 9.3 months (95% CI, 5.8-20.5), 11.1 months (95% CI, 7.9-18.5), and 5.7 months (95% CI, 5.6-6.2), respectively.

Median duration of response in the PD-L1-high population in the durvalumab only, durvalumab plus tremelimumab, and chemotherapy groups was 18.5 months (95% CI, 7.6-not estimable), 10.0 months (95% CI, 7.4-18.7), and 5.8 months (95% CI, 5.1-7.0), respectively.

Treatment-related adverse events occurred in 56% of the durvalumab cohort, 75% of the durvalumab plus tremelimumab cohort, and 90% of the chemotherapy cohort. Both durvalumab monotherapy and durvalumab/tremelimumab had manageable safety profiles, and no new safety signals were observed.

Reflecting on the results, Powles commented, “Overall, with a median survival 41 months, this DANUBE data has the most robust data set to date. I think it gives a good impression of the role of both monotherapy and the combination in this environment.”

He added, “While the trial was negative, it does give us some provocative data…for future trials."

1. Powles TB, van der Heijden MS, Gauna Castellano D, et al. A phase III, randomized, open-label study of first-line durvalumab (D) with or without tremelimumab (T) vs standard of care chemotherapy in patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE). Paper presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 697O.

2. Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. 

. 2017;18(11):1483-1492. doi:10.1016/S1470-2045(17)30616-2

3. Balar AV, Galsky MD, Rosenberg JE, IMvigor 210 Study Group. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. 

. 2017; 389(10064)67-76. doi: 10.1016/S0140-6736(16)32455-2

4. Sharma P, Sohn J, Shin SJ, et al. Efficacy and tolerability of tremelimumab in locally advanced or metastatic urothelial carcinoma patients who have failed first-line platinum-based chemotherapy. 

. 2020;26-61-70. doi:10.1158/1078-0432.CCR-19-1635

5. Balar AV, Mahipal A, Grande E, et al. Durvalumab + tremelimumab in patients with metastatic urothelial cancer. Paper presented at: 2018 American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago, IL.

The co-primary end points of overall survival in patients with metastatic urothelial cancer were not met in the phase 3 DANUBE trial of durvalumab in combination with tremelimumab and durvalumab monotherapy, according to results presented at the 2020 ESMO Virtual Congress.

Benjamin Saylor | Authors

Articles

Long-Term Responders of Apalutamide Identified With Molecular Signature in nmCRPC

Apalutamide With ADT Maintains OS Benefit in mCSPC

In ARAMIS Trial, Crossover Has Minimal Impact on Darolutamide OS Benefit

Durvalumab With or Without Tremelimumab Fails to Meet OS Endpoints in Urothelial Cancer