FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma.

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multi-cohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR) determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% CI: 59, 76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.

US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.

Efficacy of Poly(ADP-ribose) Polymerase Inhibitors by Individual Genes in Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer: A US Food and Drug Administration Pooled Analysis.

PURPOSE: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. PATIENTS AND METHODS: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. RESULTS: In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). CONCLUSION: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.

Cytoreductive nephrectomy in the era of immune checkpoint inhibitors: a U.S. FDA pooled analysis.

BACKGROUND: This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) with or without cytoreductive nephrectomy (CN) prior to a combination of immune checkpoint inhibitor (ICI) and anti-angiogenic therapy. METHODS: Five trials of ICI plus anti-angiogenic therapy were pooled. Only patients with stage 4 at initial diagnosis were included to ensure that nephrectomy was done for cytoreductive purposes and not to previously treat an earlier stage of disease. Effect of CN prior to ICI on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and presence of sarcomatoid differentiation. RESULTS: A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively, and the adjusted hazard ratio (HR) was 0.71 (95% CI: 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively, and the adjusted HR was 0.63 (95% CI: 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without CN. CONCLUSIONS: Patients with mRCC with CN prior to ICI plus anti-angiogenic therapy had improved outcomes compared to patients without CN. Selection factors for CN may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior CN may be considered when designing clinical trials to assess impact of this factor on prognosis.

A Pooled Analysis of Treatment-Free Survival in Advanced Renal Cell Carcinoma.

PURPOSE: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). PATIENTS AND METHODS: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. RESULTS: Three trials met criteria for analysis; 1183 pts received IO-TKI versus 1184 on control arms received TKI alone (sunitinib [SUN]). IO-TKI and SUN groups spent 9% (2.7 months [95% confidence interval (CI): 1.8, 3.5]) and 10% (2.9 months [95% CI: 2.1, 3.8]) of the 30-mo period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. CONCLUSIONS AND RELEVANCE: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared to the SUN group. These findings may reflect continuation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in 2 trials.

FDA Approval Summary: Olaparib in Combination With Abiraterone for Treatment of Patients With BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.

Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development.

SUMMARY: Cancer drug development remained robust in 2023. Highlights of U.S. drug approvals this year include new immunotherapies and targeted drug development in adult and pediatric patients as well as patients with rare diseases.

A U.S. Food and Drug Administration-pooled Analysis of Frontline Combination Treatment Survival Benefits by Risk Groups in Metastatic Renal Cell Carcinoma.

BACKGROUND: While frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease. OBJECTIVE: We aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis. DESIGN, SETTING, AND PARTICIPANTS: We pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021. INTERVENTION: All trials used IO/TKI combinations as the treatment option and sunitinib as the control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group. RESULTS AND LIMITATIONS: In this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups. CONCLUSIONS: The frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed. PATIENT SUMMARY: Patients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature.

FDA Approval Summary: Lutetium Lu 177 Vipivotide Tetraxetan for Patients with Metastatic Castration-Resistant Prostate Cancer.

On March 23, 2022, the FDA approved Pluvicto (lutetium Lu 177 vipivotide tetraxetan, also known as 177Lu-PSMA-617) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. The recommended 177Lu-PSMA-617 dose is 7.4 gigabecquerels (GBq; 200 mCi) intravenously every 6 weeks for up to six doses, or until disease progression or unacceptable toxicity. The FDA granted traditional approval based on VISION (NCT03511664), which was a randomized (2:1), multicenter, open-label trial that assessed the efficacy and safety of 177Lu-PSMA-617 plus best standard of care (BSoC; n = 551) or BSoC alone (n = 280) in men with progressive, PSMA-positive mCRPC. Patients were required to have received ≥1 androgen receptor pathway inhibitor, and one or two prior taxane-based chemotherapy regimens. There was a statistically significant and clinically meaningful improvement in overall survival (OS), with a median OS of 15.3 months in the 177Lu-PSMA-617 plus BSoC arm and 11.3 months in the BSoC arm, respectively (HR: 0.62; 95% confidence interval: 0.52-0.74; P < 0.001). The most common adverse reactions (≥20%) occurring at a higher incidence in patients receiving 177Lu-PSMA-617 were fatigue, dry mouth, nausea, anemia, decreased appetite, and constipation. The most common laboratory abnormalities that worsened from baseline in ≥30% of patients receiving 177Lu-PSMA-617 were decreased lymphocytes, decreased hemoglobin, decreased leukocytes, decreased platelets, decreased calcium, and decreased sodium. This article summarizes the FDA review of data supporting traditional approval of 177Lu-PSMA-617 for this indication.

U.S. FDA Drug Approvals for Gynecological Malignancies: A Decade in Review.

Over the last decade, there has been tremendous progress in the treatment of patients with gynecologic cancers with a changing therapy landscape. This summary provides an overview of U.S. Food and Drug Administration (FDA) approvals for gynecologic cancers from 2010 to 2020, totaling 17 new indications. For each of the approved indications, endpoints, trial design, results, and regulatory considerations are outlined. Among these 17 indications, six received accelerated approval (AA) and 11 received regular approval (RA). As of September 2021, of the six AA, three have subsequently demonstrated clinical benefit resulting in conversion to RA and the remaining three have ongoing clinical trials that have not yet reported results. Approval decisions for these 17 indications were supported by primary efficacy endpoints of progression-free survival (n = 10), objective response rate (n = 6), and overall survival (n = 1) and showed a favorable benefit-risk profile. Among the 17 indications, 15 received priority review and three applications participated in one or more novel Oncology Center of Excellence initiatives, including Real Time Oncology Review, Assessment Aid, and Project Orbis. Current FDA thinking on drug development opportunities and regulatory initiatives currently under way will be discussed.

Refining neoadjuvant therapy clinical trial design for muscle-invasive bladder cancer before cystectomy: a joint US Food and Drug Administration and Bladder Cancer Advocacy Network workshop.

The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.

Survival outcomes in older men with non-metastatic castration-resistant prostate cancer treated with androgen receptor inhibitors: a US Food and Drug Administration pooled analysis of patient-level data from three randomised trials.

BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.

FDA Approval Summary: Olaparib Monotherapy or in Combination with Bevacizumab for the Maintenance Treatment of Patients with Advanced Ovarian Cancer.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)-positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. IMPLICATIONS FOR PRACTICE: These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient-positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

Regulatory Considerations for Contribution of Effect of Drugs Used in Combination Regimens: Renal Cell Cancer Case Studies.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

An FDA Review of Drug Development in Nonmetastatic Castration-resistant Prostate Cancer.

The FDA has approved three androgen receptor inhibitors-enzalutamide, apalutamide, and darolutamide-for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

Exploration of baseline patient-reported side effect bother from cancer therapy.

BACKGROUND: Patient reports of expected treatment side effects are increasingly collected as part of the assessment of patient experience in clinical trials. A global side effect item that is patient-reported has the potential to inform overall tolerability. Therefore, the aim of this study was to examine the completion and distribution of such a global single-item measure of side effect burden in five cancer clinical trials. METHODS: Data from five trials from internal Food and Drug Administration databases that included the Functional Assessment of Cancer Therapy-General single-item measure of overall side effect burden (i.e. impact on degree of bother) were analyzed. Completion rates for the side effect bother item, items adjacent to this item, and two non-adjacent items on the Functional Assessment of Cancer Therapy-General that are related to health-related quality of life were calculated at the baseline assessment and at the 3-month assessment. To evaluate the distribution, the percentage of patients reporting high levels (quite a bit or very much bother) of side effect bother at baseline and 3 months was assessed. RESULTS: Completion rates for all items were at least 80% regardless of time point or trial population. However, in three of the five trials, completion rates for the side effect bother item were lower at baseline compared to adjacent and non-adjacent items. This difference was not observed at 3 months. Up to 9.4% of patients reported high levels of side effect bother at baseline. CONCLUSION: Patients may enter trials already reporting some bother from side effects. This can make interpretation of results with respect to the investigational agent under study challenging. Patients may skip an item evaluating side effect bother at baseline, suggesting some difficulty with interpretation of what is being asked. Further study of the wording and utility of a baseline side effect bother assessment is warranted.

Development of Treatments for Localized Prostate Cancer in Patients Eligible for Active Surveillance: U.S. Food and Drug Administration Oncology Center of Excellence Public Workshop.

PURPOSE: The following is a summary of discussion at a United States FDA (Food and Drug Administration) public workshop reviewing potential trial designs and end points to develop therapies to treat localized prostate cancer. MATERIALS AND METHODS: The workshop focused on the challenge that drug and device development to treat localized prostate cancer has been limited by the large trial sizes and lengthy timelines required to demonstrate an improvement in overall or metastasis-free survival and by the lack of agreed on alternative end points. Additionally, evolving treatment paradigms in the management of localized prostate cancer include the widespread use of active surveillance of patients with low and some intermediate risk prostate cancer, and the availability of advances in imaging and genomics. RESULTS: The workshop addressed issues related to trial design in this setting. Attendees discussed several potential novel end points such as a delay of morbidity due to radiation or prostatectomy and pathological end points such as Gleason Grade Group upgrade. CONCLUSIONS: The workshop provided an open forum for multiple stakeholder engagement to advance the development of effective treatment options for men with localized prostate cancer.

Global Variation in Opioid Use in Prostate Cancer Trials.

IMPORTANCE: Regional variation in opioid use may be attenuated when pharmaceutical-sponsored trials include care that is often standardized by protocols. Understanding such variation is important for global trials that sometimes include time to opioid use as an end point. OBJECTIVE: To identify whether regional and country-level variation in opioid use exists among prostate cancer clinical trials across the world. DESIGN, SETTING, AND PARTICIPANTS: International phase 3 randomized clinical trials with patients with metastatic prostate cancer and initiation from January 1, 2008, or later were identified through internal databases of the US Food and Drug Administration. Data of patients in the intention-to-treat population from each trial were pooled. Descriptive and regression analyses of the collected data were conducted from September 2018 to February 2019. EXPOSURES: Cancer therapy. MAIN OUTCOMES AND MEASURES: Opioid use data were from concomitant medications reported in the database for each trial. Logistic regression models, descriptive statistics, and χ2 tests were used to compare opioid use across world regions while adjusting for patient age, presence of visceral disease, bony disease, and baseline Eastern Cooperative Oncology Group Performance Status score and pain score. RESULTS: In total, 9670 patients (mean [SD] age of 69.2 [8.3] years) from 8 prostate cancer clinical trials in 46 countries were included. Patients in Eastern Europe (adjusted odds ratio [AOR], 0.19; 95% CI, 0.16-0.22) and Asia (AOR, 0.31; 95% CI, 0.25-0.38) were less likely to use opioids compared with patients in North America. These findings held even when the analysis was restricted to patients who reported moderate to high pain levels at baseline (Eastern Europe: AOR, 0.16 [95% CI, 0.12-0.22]; Asia: AOR, 0.47 [95% CI, 0.29-0.79]). Within North America, rates of opioid use were similar between the United States and Canada (AOR, 1.13; 95% CI, 0.93-1.37). CONCLUSIONS AND RELEVANCE: This study found that, despite the clinical trial setting, opioid use appeared to vary by world regions, suggesting that this variability should be considered in international clinical trials.