Treatment with apalutamide (Erleada) plus androgen-deprivation therapy (ADT) reduced the risk of death by 35% versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC), according to results of the final analysis of the phase 3 randomized, double-blind, placebo-controlled TITAN trial (NCT02489318) presented at the 2021 Genitourinary Cancers Symposium.

In the TITAN trial, 1052 patients with mCSPC 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), according to investigator Kim N. Chi, MD, chief medical officer and vice president of BC Cancer, Vancouver, Canada.

For the TITAN trial (NCT02489318), 1052 patients with mCSPC 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.

 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.

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

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

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

Articles

February 13, 2021 - Treatment with apalutamide plus androgen-deprivation therapy reduced the risk of death by 35% versus ADT alone in patients with metastatic castration-sensitive prostate cancer.

Apalutamide Demonstrates Sustained Survival Benefit in mCSPC

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

The FDA approved darolutamide 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.

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

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

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

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

February 12, 2021 - Crossover from placebo to darolutamide appeared to have minimal impact on the overall survival benefit experienced by patients with nonmetastatic castration-resistant prostate cancer who were enrolled to the pivotal phase 3 ARAMIS trial.

Crossover Minimally Impacts OS Benefit Achieved With Darolutamide in ARAMIS Trial

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.

Data from the phase 3 DANUBE trial were presented at the 2020 European Society for Medical Oncology virtual congress.

In introducing the 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.

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.

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

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

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

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.

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

Urothelial Cancer Treatment Combination Fails To Meet OS End Points

The benefits conferred by the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) for the first-line treatment of advanced renal cell carcinoma (RCC) remained durable after 4-year follow-up compared with treatment with sunitinib (Sutent).

Investigators also reported that a subgroup of patients with 1 or more target kidney lesions experienced kidney tumor reduction and other benefits from the combination treatment.

The research was presented at the 2020 European Society for Medical Oncology virtual congress.

“Nivolumab plus ipilimumab was the first immunotherapy combination to demonstrate an overall survival advantage over sunitinib in intermediate- and poor-risk patients with advanced renal cell carcinoma,” CheckMate-214 investigator Laurence Albiges, MD, PhD, said in a press release.

 “Now, after 4 years, the durable efficacy seen in CheckMate-214 represents important progress towards the aim of changing survival expectations for these patients,” added Albiges, Head of Genitourinary Unit, Gustave Roussy Institute, Villejuif, France.

The randomized, open-label phase 3 CheckMate-214 trial evaluated the combination of nivolumab and ipilimumab versus sunitinib in patients with previously untreated advanced or metastatic RCC.

Patients in the combination group (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for 4 doses followed by 3 mg/kg nivolumab every 2 weeks. Patients in the sunitinib group (n = 546) received 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment. Treatment was given until progression or unacceptable toxic effects.

Primary end points included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in an intermediate- to poor-risk patient population. In addition, non-prespecified, post hoc exploratory efficacy analyses were performed in a subgroup of study patients who had not undergone prior nephrectomy and who had 1 or more target kidney lesions.

In intermediate- to poor-risk patients treated with nivolumab/ipilimumab, median OS was 48.1 months, compared with 26.6 months in patients who received sunitinib (HR, 0.65; 95% CI, 0.54-0.78). The 4-year OS rate for the combination treatment and sunitinib groups was 50.0% and 35.8%, respectively. ORR was also higher in patients receiving combination treatment versus sunitinib, with more ongoing responses in intermediate- to poor-risk patients (65% vs 50%, respectively). Median duration of response was not reached in the combination treatment arm and was 19.7 months for sunitinib.

Analysis of patients in the intention-to-treat (ITT) population with 48 months’ follow-up also pointed to the benefits of nivolumab/ipilimumab treatment. Median OS was not reached for all patients in the combination treatment group vs 38.4 months in the sunitinib group (HR, 0.69; 95% CI, 0.59-0.81), with 4-year OS rates of 53.4% and 43.3%, respectively. ORR was higher in patients receiving nivolumab/ipilimumab, with more ongoing responses compared to patients receiving sunitinib (65% vs 52%). Median duration of response was not reached in patients treated with nivolumab/ipilimumab and was 23.7 months in the sunitinib group.

In the subgroup of patients with 1 or more target kidney lesions, ORR was 34% in the nivolumab/ipilimumab group vs 15% in the sunitinib group. A 30% or greater reduction in target kidney lesion(s) was observed in 35% of patients receiving the combination treatment vs 20% in patients receiving sunitinib.

Treatment-related adverse events of any grade occurred in 94% of patients receiving combination treatment and 97.0% of patients receiving sunitinib, and no new safety signals emerged over the longer follow-up.

“We have now evaluated Opdivo plus Yervoy in multi-year phase 3 trials across RCC, melanoma, non-small cell lung cancer, and mesothelioma, and in all of these studies, we have seen improved survival compared to the existing standard of care,” said Nick Botwood, MD, vice president, interim head, Oncology Development, Bristol Myers Squibb, in a press release. “The 4-year results from CheckMate -214 build on our understanding of and leadership in addressing advanced RCC, reinforcing the potential for durable, long-term survival benefits with Opdivo plus Yervoy in the first-line setting. Taken as a whole, these data provide further evidence for the value of distinct but complementary dual checkpoint inhibition in the treatment of advanced cancers.”

Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma 711P in CheckMate 214: 4-year follow-up and subgroup analysis of patients without nephrectomy. Presented at: European Society of Medical Oncology virtual congress; September 19-21, 2020. Abstract 711P.

Bristol Myers Squibb. Four-year data continue to show superior, long-term survival benefit with Opdivo (nivolumab) plus Yervoy (ipilimumab) in patients with previously untreated advanced or metastatic renal cell carcinoma. Press release. September 17, 2020. Accessed September 18, 2020. https://bit.ly/3mCwhwO.

The benefits conferred by the combination of nivolumab and ipilimumab for the first-line treatment of advanced renal cell carcinoma remained durable after 4-year follow-up compared with treatment with sunitinib.

Benjamin Saylor

Articles

Apalutamide Demonstrates Sustained Survival Benefit in mCSPC

Crossover Minimally Impacts OS Benefit Achieved With Darolutamide in ARAMIS Trial

Urothelial Cancer Treatment Combination Fails To Meet OS End Points

Nivolumab/Ipilimumab Combo Shows Durable Benefit at 4 Years in Advanced RCC