Does inhibition of ataxia telangiectasia and Rad3 complement cisplatin-based chemotherapy for metastatic urothelial cancer?
In this open-label, phase 2 randomized clinical trial, 87 patients with metastatic urothelial cancer received cisplatin with gemcitabine chemotherapy with or without berzosertib, an ataxia telangiectasia and Rad3 inhibitor. The primary end point of the study was progression-free survival; no significant difference was observed and a trend toward inferior survival was observed with the addition of berzosertib.
The findings of this trial indicate that the addition of berzosertib does not add to the efficacy of cisplatin and gemcitabine chemotherapy in patients with metastatic urothelial cancer, likely because of added hematologic toxic effects with the combination resulting in substantial dose reductions.
Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer.
To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine.
Design, Setting, and Participants
In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020.
In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle.
Main Outcomes and Measures
The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy.
Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001).
Conclusions and Relevance
The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine.
ClinicalTrials.gov Identifier: NCT02567409
The role of cisplatin-based chemotherapy for metastatic urothelial cancer (mUC) was established several decades ago, and it continues to represent the standard of care for cisplatin-eligible patients.1,2 Although multiple novel therapies (eg, targeted therapies, antibody-drug conjugates, and immunotherapy) have been introduced for mUC, these remain relegated to either maintenance or salvage therapy for patients receiving cisplatin-based chemotherapy.3-6 Attempts to combine novel therapies with cisplatin-based chemotherapy have not been shown to extend survival, perhaps the most notable examples being 2 separate phase 3 trials comparing cisplatin and gemcitabine with or without the checkpoint inhibitors pembrolizumab and atezolizumab, or cisplatin and gemcitabine with or without the angiogenesis inhibitor bevacizumab.7-9
The impetus for building on the cisplatin and gemcitabine foundation is that most patients receiving this regimen will not be cured of their disease. Because both cisplatin and gemcitabine induce DNA damage, albeit through distinct mechanisms, one potential approach is to interfere with mechanisms that cause DNA repair. Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) represent 2 master regulators of DNA damage repair; although ATM is principally involved in the response to double-stranded DNA breaks, ATR responds to single-stranded DNA and a variety of other damage elements.10 Both ATM and ATR are PI3K-like protein kinases, and pharmacologic strategies have been developed to antagonize each. Herein, we focus on berzosertib, a first-in-class ATR inhibitor that inhibits its target at micromolar doses (50% inhibitory concentration, 0.019 μM).11 Berzosertib has been shown to lower the mean 50% inhibitory concentration of cisplatin by approximately 1.5-fold. Murine studies using lung tumor xenografts have shown substantial synergy between cisplatin and berzosertib.12 Preclinical studies also support synergy between gemcitabine and ATR inhibitors.13,14
A phase 1 study of berzosertib enrolled 40 patients with advanced cancer, with 17 patients receiving monotherapy and the remainder receiving berzosertib with carboplatin.15 In this heavily pretreated population, 1 patient with advanced colorectal cancer achieved a durable complete response with berzosertib monotherapy lasting 29 months. A large proportion of additional patients had stable disease as their best response. Given the activity observed with berzosertib in this early study, as well as the preclinical synergy observed between berzosertib and cisplatin and gemcitabine, we sought to determine whether the addition of berzosertib to chemotherapy in patients with mUC could improve clinical outcomes.
The study was an open-label, phase 2 randomized clinical trial conducted through the US National Cancer Institute’s Experimental Therapeutics Clinical Trials Network. A total of 23 centers participated in the study. To be eligible, patients aged 18 years or older had to have histologically or cytologically confirmed mUC with measurable disease. Patients may not have had cytotoxic therapy for metastatic disease, and at least 12 months must have elapsed since platinum-based perioperative treatment. Eligible patients had a Karnofsky Performance Status (KPS) level greater than or equal to 70% and an anticipated life expectancy of greater than 6 months. Patients were required to meet generally established criteria for cisplatin eligibility, including creatinine clearance of greater than or equal to 50 mL/min, no symptomatic congestive heart failure, no preexisting neuropathy (grade 2 or greater), and performance status criteria as noted previously.
The study was approved by the National Cancer Institute’s Central Institutional Review Board and the US Food and Drug Administration. All patients were required to supply written informed consent before participating, and all procedures were undertaken in accordance with the Declaration of Helsinki.16 Participants did not receive financial compensation. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized clinical trials.
Patients were randomized in a 1:1 fashion to receive either cisplatin and gemcitabine alone (arm B) or cisplatin and gemcitabine with berzosertib (arm A). Patients were stratified using a permuted block design based on Bajorin risk category (0 = KPS ≥80 and no visceral metastases; 1 = KPS <80 or visceral metastases [but not both]; and 2 = both KPS <80 and presence of visceral metastases). In control arm B, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In experimental arm A, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, was given on days 1 and 8; and berzosertib, 90 mg/m2, was given on days 2 and 9 of a 21-day cycle. Although cisplatin and gemcitabine could be administered as per institutional guidelines (with associated premedications at the investigators’ discretion), berzosertib was administered over 1 hour. The use of growth factor support was encouraged but not mandated.
Dose modifications were permitted for cisplatin and gemcitabine and berzosertib. Patients in the control arm were allowed dose reductions of cisplatin to 60 and 50 mg/m2, and dose reductions of gemcitabine to 875 mg/m2 and 600 mg/m2 were permitted. Patients in the experimental arm were allowed dose reductions of cisplatin to 50 and 40 mg/m2 and dose reductions of gemcitabine to 600 and 500 mg/m2. The berzosertib dosage could be reduced to 72 and 60 mg/m2. Treatment was continued for a total of 6 cycles unless early discontinuation was warranted on the basis of disease progression, intercurrent illness, unacceptable adverse events, or patient withdrawal.
Baseline imaging included computed tomography of the chest, abdomen, and pelvis, as well as a bone scan as clinically indicated. Following baseline imaging, patients were assessed for response using the same modality every 9 weeks for 6 months and then every 12 weeks thereafter. Patients were followed up for up to 36 months after protocol-based therapy or until death. Response was evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Safety evaluations were conducted on days 1 and 8 of every cycle, and laboratory assessments were additionally performed on day 15 of each cycle.
The primary objective of the study was to determine whether PFS (based on all patients who started protocol treatment) was improved with the addition of berzosertib to cisplatin and gemcitabine compared with cisplatin and gemcitabine alone. Based on previously published meta-analytic data with cisplatin-based chemotherapy, it was assumed that the median PFS in the control arm would be approximately 5.3 months.17 With 90 patients accrued and 80 evaluable for the primary end point, we would have 90% power to detect an improvement in median PFS from 5.3 months with cisplatin and gemcitabine alone to 10.1 months with cisplatin and gemcitabine plus berzosertib. This assumed a 1-sided α level of 0.1 and uniform accrual over 2 years with 9 additional months of follow-up. A prespecified interim analysis occurred after 40 events, with stopping rules in place for both futility and success based on estimates of PFS. Details of this analysis can be found in the full protocol (Supplement 1).
Progression-free survival was defined as the time from randomization to progression or death, whichever occurred first. Overall survival was defined as the duration of time from randomization to death from any cause. Toxic effects were assessed and graded using the Common Terminology Criteria for Adverse Events, version 4.0. Progression-free survival and OS were summarized using the Kaplan-Meier method and Cox proportional hazards regression (stratified by Bajorin risk) was used to compare treatment arms (log-rank test), and response rate (RR) was compared using the Fisher exact test. Toxic effects comparisons between the 2 arms were conducted using the Fisher exact test when the presence of toxic effects was dichotomized and using the Cochran-Armitage test for trend if all grades were considered. Median follow-up was calculated by reverse Kaplan-Meier analysis.
Between January 27, 2017, and December 12, 2019, 91 patients were enrolled in the study; before starting treatment, 1 patient no longer met the eligibility criteria and 3 patients withdrew consent from treatment (Figure 1). Eighty-seven patients were ultimately randomized and received cisplatin and gemcitabine alone (41 patients, arm B) or cisplatin and gemcitabine plus berzosertib (46 patients, arm A). The median age of the study population was 67 (range, 32-84) years, 68 patients (78%) were men, 19 patients (22%) were women, and most patients (74 [85%]) were of White race. The KPS performance status was 90% to 100% in two-thirds of the study population, with only 4 patients (2 in each arm) with a KPS level of 70%. No substantial differences in patient characteristics were seen, as delineated in Table 1.
At the time of data cutoff on December 15, 2020, all patients had discontinued study treatment, with a median follow-up of 18.9 months (IQR, 9.9-27.4 months) overall. Median PFS with cisplatin and gemcitabine was 8.0 months (95% CI, 6.8- NA months) and for cisplatin, gemcitabine, and berzosertib was 8.0 months (95% CI, 6.0-14.4 months). The unstratified hazard ratio (HR) (relative to control, arm B), was 1.17 (95% CI, 0.69-1.98; P = .55) (Figure 2A). The stratified HR incorporating Bajorin risk criteria was 1.22 (95% CI, 0.72-2.08). Median OS was longer with cisplatin and gemcitabine alone compared with cisplatin and gemcitabine with berzosertib (19.8 [95% CI, 14.8-NA] vs 14.4 [95% CI, 10.0-NA] months); the unadjusted HR (relative to control, arm B) was 1.33 (95% CI, 0.71-2.48; P = .37) (Figure 2B); Bajorin-adjusted HR (relative to control, arm B) was 1.42 (95% CI, 0.76-2.68). Progression-free survival and OS between the 2 arms were also summarized by subgroups of age, Bajorin risk, and KPS (eTable in Supplement 2). The median duration of therapy was 3.9 months (IQR, 2.3-4.2 months) in the control arm and 3.7 months (IQR, 2.0-4.3 months) in the experimental arm.
In patients receiving cisplatin and gemcitabine alone, 26 patients achieved a response for an overall RR of 63% (95% CI, 0.47-0.78 months). Four patients (9.8%) achieved a complete response. In patients receiving cisplatin and gemcitabine plus berzosertib, 25 patients achieved a response, for an overall RR of 54% (95% CI, 0.39%-0.69%). Four patients (8.7%) in arm A achieved a complete response. No significant difference was noted in overall RR between the control and experimental groups (P = .51).
There were 2 grade 5 adverse events unrelated to disease progression. One patient in arm A experienced a cardiac arrest before berzosertib administration on day 2, and 1 patient in arm B developed multiorgan failure a week after starting treatment. The remainder of the safety data are reported in Table 2. The cumulative rate of grade 3/4 adverse events was significantly higher with cisplatin and gemcitabine plus berzosertib compared with cisplatin and gemcitabine alone, with 42 of 46 (91%) vs 27 of 41 (66%) (P < .01). The most notable difference between the control and experimental arms was hematologic toxic effect. The rate of grade 3/4 treatment-related thrombocytopenia was 59% with cisplatin and gemcitabine plus berzosertib, compared with 39% with cisplatin and gemcitabine alone. The rate of grade 3/4 treatment-related neutropenia was similarly higher with the addition of berzosertib (37% vs 27%).
The percentage of patients requiring dose reductions was 35% (n = 16) for cisplatin, 61% (n = 28) for gemcitabine, and 20% (n = 9) for berzosertib in arm A. Dose reductions occurred for 34% (n = 14) of patients receiving cisplatin and 54% (n = 22) of patients in arm B. Growth factors were used in 23 of 46 patients (50.0%) in arm A and 14 of 41 patients (34.1%) in arm B. Six cycles of therapy were delivered to 25 of 46 patients (54.3%) in arm A and 23 of 41 patients (56.1%) in arm B. Figure 3 depicts an exploratory analysis of cumulative cisplatin dose in both study arms. Patients in the arm B had a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in arm A (P < .001). Without dose modifications, the anticipated cumulative cisplatin doses across a planned 6 cycles of therapy would have been 360 mg/m2 in arm B and 420 mg/m2 in arm A; the doses of cisplatin ultimately rendered therefore reflect 69% and 88% of planned dosing on the study arms.
Our study showed no improvement in PFS or RR with the addition of berzosertib to cisplatin and gemcitabine in patients with mUC. Of concern, a trend toward inferior survival was noted with the addition of berzosertib. In addition, significantly higher rates of high-grade adverse events (primarily hematologic) were noted in patients receiving berzosertib. These results are unexpected given the synergy between chemotherapy and berzosertib demonstrated across preclinical studies, as previously noted.
The second largest clinical evaluation of berzosertib thus far was in a randomized phase 2 study in patients with platinum-refractory ovarian cancer.18 Patients received either gemcitabine alone (n = 36) or gemcitabine with berzosertib (n = 34). Although the study met its primary end point, demonstrating an improvement in PFS from 14.7 weeks to 22.9 weeks with the addition of berzosertib (HR, 0.57; 90% CI, 0.33-0.98; 1-sided P = .04), overall RR was inferior in the experimental arm (3% with gemcitabine plus berzosertib vs 11% with gemcitabine alone). No significant difference in OS was observed in this study, although (in contrast to our study) the trend favored berzosertib, particularly in patients who had a shorter platinum-free interval.
The largely conflicting results of our study and the ovarian cancer experience18 could be associated broadly with 2 factors, the first being broad biological differences between the 2 diseases. Ovarian cancer represents a disease heavily enriched in DNA damage repair (DDR) alterations, manifesting clinically in the broad activity of polyadenosine diphosphate-ribose polymerase inhibitors in unselected patients.19,20 Recent studies suggest the frequency of both somatic and germline DDR alterations in bladder cancer may be higher than previously thought.21,22 However, the activity of polyadenosine diphosphate-ribose polymerase inhibitors (and now, ATR inhibitors) appears to be modest in an unselected population. A phase 2 study of rucaparib including 96 evaluable patients had a best response or stable disease in 27 patients (28.1%), and PFS was only 1.8 months.23 The 16-week clinical benefit rate was 16% in patients with DDR alterations compared with 7% in patients with wild-type DDR. A future study may prospectively identify patients with DDR alterations for treatment with berzosertib. The phase 1 study of the compound identified a complete response in a patient with metastatic colorectal cancer bearing an ATM mutation15; it has been suggested that these mutations could confer synthetic lethality with ATR inhibitors.12,15 Cell lines with p53 deficiency also appear to be more sensitive to ATR inhibition.24 Therefore, there are several candidate genes that could be evaluated in biomarker-based designs.
The second factor differentiating the ovarian and urothelial cancer results is clinical—simply put, the regimen of cisplatin and gemcitabine plus berzosertib evaluated in the present study elicited too much myelosuppression. The potential for hematologic toxic effects with platinum and berzosertib was known from previous phase 1 data.15 At the outset of the trial, we attempted to mitigate this potential by decreasing the doses of cisplatin and gemcitabine in the arm including berzosertib. This action alone may have dissipated the clinical impact of berzosertib; as noted, the cumulative doses of cisplatin were significantly lower in the experimental arm of the study (Figure 3). Even with this initial dose reduction, the rate of grade 3/4 thrombocytopenia was notably higher in the berzosertib arm. The dose reductions and treatment discontinuations that ensued because of this could have certainly compromised efficacy. The ovarian cancer study used a base regimen of gemcitabine.18 Compared with gemcitabine monotherapy, the combination of gemcitabine with berzosertib elicited a higher rate of grade 3/4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%). However, these proportions compare favorably with the rates of toxic effects incurred in our trial. A lesson derived from this trial is that excessive attenuation of cisplatin dosing should be avoided whenever feasible.
Limitations and Strengths
Although our sample size might be cited as a limitation, our study points to the importance of randomized phase 2 designs. A recent development in clinical trials has been to move from phase 1 to phase 3, bypassing intermediate evaluations. The randomized phase 2 design offers an opportunity to more efficiently estimate the potential of a novel regimen before hundreds more patients are enrolled in a phase 3 trial.
Our phase 2 randomized clinical trial provides evidence that berzosertib in combination with cisplatin and gemcitabine does not warrant further study. Instead, future efforts should focus on biomarker-based designs evaluating either monotherapy or rational combinations with less myelosuppression.
Accepted for Publication: June 1, 2021.
Published Online: August 26, 2021. doi:10.1001/jamaoncol.2021.3441
Corresponding Author: Sumanta K. Pal, MD, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd, Duarte, CA 91010 (firstname.lastname@example.org).
Author Contributions: Dr Pal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Pal, Frankel, Michaelson, Newman, Lara.
Acquisition, analysis, or interpretation of data: Pal, Frankel, Mortazavi, Milowsky, Vaishampayan, M. Parikh, Lyou, Wang, R. Parikh, Teply, Dreicer, Emamekhoo, Hoimes, Zhang, Srinivas, Kim, Cui, Newman, Lara.
Drafting of the manuscript: Pal, Frankel, Cui, Lara.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Pal, Frankel, Cui.
Obtained funding: Newman, Lara.
Administrative, technical, or material support: M. Parikh, Lyou, Srinivas, Newman, Lara.
Supervision: Michaelson, Newman, Lara.
Conflict of Interest Disclosures: Dr Pal reported receiving fees for serving on the advisory boards of Pfizer, Novartis, Aveo, Genentech, Exelixis, Bristol-Myers Squibb, Astellas Pharma, Roche, and Ipsen outside the submitted work. Dr Mortazavi reported other from NIH. The study was an NIH-sponsored trial, and supported by our institutional UM1 NIH Grant during the conduct of the study; research funding to the institution from Acerta Pharma, Genentech, Roche, Merck Novartis, Seattle Genetics, Astellas Pharma, Mirati Therapeutics, Bristol-Myers Squibb, and Debiopharm Group; and fees for serving on the advisory boards of Seattle Genetics, Pfizer, and Debiopharm Group outside the submitted work. Dr Milowsky reported receiving grants to the institution from Merck, Roche/Genentech, Bristol-Myers Squibb, Astellas Pharma, Clovis Oncology, Inovio Pharmaceuticals, Mirati Therapeutics, Constellation Pharmaceuticals, Syndax, Incyte, Amgen, Regeneron, Arvinas, Seagen, Pfizer, and Johnson & Johnson/Janssen outside the submitted work. Dr Vaishampayan reported receiving personal fees from BMS, Exelixis, Bayer, Sanofi, Genentech, AAA, and Alkermes, and grants from Merck and Astellas outside the submitted work. Dr M. Parikh reported receiving consulting fees from Janssen, Oncocyte, and Seagen outside the submitted work. Dr Lyou reported receiving personal fees from Pfizer and Seattle Genetics outside the submitted work. Dr Teply reported receiving personal fees from AstraZeneca and Janssen outside the submitted work. Dr Dreicer reported receiving personal fees from Astellas, Bayer, Eisai, EMD, Serono, Exelixis, GIlead, Hinova, Infinity, Janssen, Merck, Myovant, Pfizer, Propella, and Tavanta outside the submitted work. Dr Emamekhoo reported receiving consulting fees from BMS, Exilexis, Seattle Genetics, and Bayer outside the submitted work. Dr Zhang reported receiving grants from NCI UM1 during the conduct of the study; grants from Genentech, Pfizer, Janssen, Acerta, Abbvie, Novartis, Merrimack, OmniSeq, PGDx, Merck, Mirati, Astellas, and Regeneron; personal fees from Exelixis, Genomic Health, Sanofi Aventis, and Astra Zeneca, Bayer, Foundation Medicine, Amgen, MJH Associates, Merck, Bristol-Myers Squibb, Pharmacyclics, SeaGen, Calithera, and Dendreon outside the submitted work; and spouse is cofounder and stockholder of both Capio Biosciences and Archimmune Therapeutics. Dr Kim reported holding stock and having other ownership interests in Abbvie, Abbott, Amgen, Arvinas, BeiGene, Bristol-Myers Squibb, Bluebird Bio, FibroGen, Illumina, Johnson & Johnson, Myovant, Natera, Oramed, Syndax, and Zentalis; receiving consulting or advisory fees from H3 Biomedicine, Takeda; Foundation Medicine, and GeneCentric; receiving research funding from Acerta, Foundation Medicine, GeneCentric, and Merck; and fees for travel, accommodations, and expenses from H3 Biomedicine and Takeda. No other disclosures were reported.
Funding/Support: This study was supported by the National Institutes of Health, National Cancer Institute under cooperative agreements with the Cancer Therapy Evaluation Program (grants UM1CA186717 and NO1-CM-2011-00038) and Cancer Center Support (grants P30 CA033572, City of Hope Medical Center; CA093373, UC Davis Medical Center).
Role of the Funder/Sponsor: Merck KGaA provided support to the study through a Cooperative Research and Development Agreement with NCI. Merck KGaA, Darmstadt, Germany, reviewed the manuscript for medical accuracy before journal submission.
Disclaimer: The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.
Data Sharing Statement: See Supplement 3.
Meeting Presentation: This work was presented at the virtual 2021 American Society of Clinical Oncology Annual Meeting; June 7, 2021.
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