AIM:This study described treatment patterns, reasons for treatment, and homologous recombination repair mutation (HRRm) testing patterns in a real-world metastatic castration-resistant prostate cancer (mCRPC) population in Europe. METHODS:Data were drawn from the Adelphi Prostate Cancer Disease Specific Programme™, a cross-sectional survey of physicians and patients conducted in France, Germany, Italy, Spain, and the United Kingdom, November 2022-May 2023. Physicians provided clinical characteristics, treatment and HRRm testing patterns, and reasons for treatment for eight consecutive patients with mCRPC. Most analyses were descriptive; treatment reasons were compared using Fisher's Exact test. RESULTS:Physicians provided data for 1,737 mCRPC patients. Most patients (73%) were androgen receptor pathway inhibitor (ARPi)-naïve at first-line (1 L) mCRPC. Here, at 1 L mCRPC, 60% of patients received ARPi and 24% chemotherapy. Of those who received ARPi prior to mCRPC (n = 291), 60% received chemotherapy at mCRPC and 21% ARPi. Overall, 37% were HRRm tested. Treatment patterns, sequencing, reasons, and HRRm testing varied by country, physician specialty, and practice setting. CONCLUSIONS:Treatment patterns generally followed guidelines. ARPi prescriptions prior to mCRPC were numerically higher than previously reported, however HRRm testing rates were still low meaning mCRPC patients may miss out on more effective targeted treatments.

92 Background: Oligometastatic hormone-sensitive prostate cancer (omHSPC) represents an advanced prostate cancer subset where metastasis-directed therapy (MDT) and prostate radiation therapy (RT) may improve clinical response and outcomes; however, there is a lack of published data on the epidemiology, clinical outcomes, and current treatment patterns. As such, we conducted a study to better characterize de novo omHSPC in the United States Veterans Affairs Health Care System (VA). Methods: This observational retrospective cohort study utilized chart abstracted data from the VA electronic medical record, as well as data from the VA Corporate Data Warehouse, a central repository of VA patient medical records. We randomly selected 400 men diagnosed with de novo mHSPC from 1/2015-12/2020. omHSPC was defined as up to 5 bone, lymph node, and/or visceral (excluding liver) metastases in total, identified by conventional imaging (bone scan, CT, and/or MRI). We estimated prevalence, described treatment patterns and used Kaplan-Meier methods to estimate overall survival (OS) and time to castration resistance from date of mHSPC diagnosis. The log rank test was used to compare differences in outcomes between omHSPC and non-omHSPC groups. Results: Of the 400 men with de novo mHSPC, 76 (19%) had omHSPC by conventional imaging. Men with omHSPC and non-omHSPC were similar in age, race, Gleason grade group, comorbidities, and metastatic site (bone and lymph node being most common). Men with non-omHSPC had a higher median PSA at mHSPC diagnosis (147.0) than omHSPC (38.3). The percentage of men on first-line (1L) novel hormonal therapy (NHT) use (most commonly abiraterone or enzalutamide) was similar between groups in the 1L setting (22.4% (omHSPC) vs 20.4% (non-omHSPC)), but the percentage of men on a 1L chemotherapy regimen was lower in omHSPC (5.3%) vs. non-omHSPC (13.6%). Overall, there was a higher percentage of men treated with MDT or prostate RT in omHSPC (13.2%) vs non-omHSPC cases (2.5%). Median OS in months (mos) was higher in men with omHSPC (55.3 mos, 95% CI 35.9-79.0) vs. non-omHSPC (25.9 mos, 95% CI 20.5-31.7, p=0.002). Median time to castration resistance was also longer in omHSPC (not reached [NR], 95% CI 42.2-NR) vs. non-omHSPC (29.3 mos, 95% CI 23.7-36.1, p=0.0014). Conclusions: Our study provides real-world insight into the prevalence, treatment patterns and clinical outcomes for omHSPC using a nationally representative VA sample. Approximately 1 in 5 men with de novo mHSPC were oligometastatic, and OS in men with omHSPC was more than double that of non-omHSPC. Although more men with omHSPC compared to non-omHSPC received potential curative therapy, the percentage was still relatively low. Future studies are warranted as several clinical trials are investigating the potential for prolonged responses with aggressive, multimodal therapy inclusive of systemic and local therapies.

131 Background: The phase 3, randomized KEYLYNK-010 trial (NCT03834519) of pembro + ola vs next-generation hormonal agent (NHA) abi or enza did not significantly improve rPFS or OS in molecularly unselected pts with mCRPC treated with prior NHA and docetaxel. The study was stopped for futility after the second prespecified interim analysis. PROs for pembro + ola vs NHA in KEYLYNK-010 are presented. Methods: Pts were randomly assigned 2:1 to receive pembro 200 mg IV Q3W for ≤35 cycles (~2 y) + ola 300 mg orally BID or NHA (either abi 1000 mg orally QD + prednisone 5 mg orally BID, if pt previously received enza, or enza 160 mg orally QD if pt previously received abi). PROs were evaluated in pts who received ≥1 dose of study treatment and had ≥1 PRO assessment. FACT-P and BPI-SF were administered at baseline, Q3W until wk 24, Q6W until wk 72, and Q12W thereafter for ≤2 y. Time to pain progression (TTPP) based on BPI-SF was a prespecified secondary end point. Prespecified exploratory end points included least squares mean (LSM) change from baseline to wk 15 for FACT-P total and subscales scores (FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS) and BPI-SF scores (pain interference, pain severity, and worst pain), and time to deterioration (TTD) and overall improvement rate in FACT-P total and subscale scores. Differences were evaluated using 2-sided nominal P values not controlled for multiplicity. Results: A total of 793 pts were randomly assigned to pembro + ola (n = 529) or NHA (n = 264). As of January 18, 2022, median follow-up was 18.7 mo (range, 6.1-31.7). In all randomized pts, completion rate for FACT-P and BPI-SF at baseline and wk 15 was >84% and >57%, respectively. No differences were observed in the median TTPP for pembro + ola (13.5 mo [95% CI, 9.7-NR]) vs NHA (12.0 mo [95% CI, 10.1-NR]; HR, 0.95 [0.72-1.26]). No LSM differences were observed in FACT-P total scores (pembro + ola, –4.62 [95% CI, –6.47 to –2.77] vs NHA, –5.86 [95% CI, –8.58 to –3.13]) or BPI-SF scores (Table). There were no differences in TTD in FACT-P total, FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS scores between groups. A numerically higher proportion of pts had improved + stable FACT-P total scores for pembro + ola (44.0%) vs NHA (39.0%). FACT-P and BPI-SF scores were generally maintained across all evaluated time points up to wk 81. Conclusions: No clinically meaningful changes from baseline were observed in HRQoL or disease-related symptom scores with either pembro + ola or NHA. PRO scores were generally similar between pembro + ola and NHA at all analyzed time points, suggesting HRQoL was maintained in heavily pretreated pts receiving pembro + ola. Clinical trial information: NCT03834519 . [Table: see text]

129 Background: The double-blind, phase 3, randomized KEYNOTE-921 trial (NCT03834506) showed that pembro + docetaxel did not significantly improve rPFS or OS for pts with mCRPC treated with prior next-generation hormonal agent (NHA) therapy. We present PROs for pembro + docetaxel vs placebo + docetaxel in KEYNOTE-921. Methods: Pts were randomly assigned 1:1 to receive pembro 200 mg or placebo IV Q3W (≤35 cycles) + docetaxel 75 mg/m2 IV Q3W (≤10 cycles) and prednisone 5 mg orally BID. PROs were evaluated in pts who received ≥1 dose of study treatment and had ≥1 PRO assessment. FACT-P and BPI-SF were administered at baseline, Q3W until wk 24, Q6W until wk 72, then Q12W for ≤2 y. A prespecified secondary end point was time to pain progression (TTPP) based on BPI-SF. Prespecified exploratory end points included least squares mean (LSM) change from baseline to wk 27 for FACT-P total and subscale scores (FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS) and wk 24 for BPI-SF scores (pain interference, pain severity, and worst pain), and time to deterioration (TTD) and overall improvement rate in FACT-P total and subscale scores. Differences were evaluated using 2-sided nominal P values not controlled for multiplicity. Results: Of 1030 pts enrolled, the PRO analysis population included 1028 (n = 514 in each arm). At the prespecified final analysis, median time from randomization to data cutoff of June 20, 2022, was 22.7 mo (range, 12.1-36.7). Completion rates for FACT-P and BPI-SF were >78% at baseline, >65% for FACT-P at wk 27, and >63% for BPI-SF at wk 24. Median TTPP was 21.1 mo (95% CI, 13.7-NR) for pembro + docetaxel vs NR (95% CI, 13.8-NR) for placebo + docetaxel (HR, 1.05 [95% CI, 0.77-1.43]). No LSM differences were observed in FACT-P total scores with pembro + docetaxel (–5.31 [95% CI, –7.02 to –3.61]) vs placebo + docetaxel (–3.89 [95% CI, –5.59 to –2.19]) or BPI-SF scores. Median TTD in FACT-P total scores was 21.8 mo (95% CI, 20.0-NR) for pembro + docetaxel and NR (95% CI, 11.1-NR) for placebo + docetaxel (HR, 1.09 [95% CI, 0.88-1.35]). No differences were observed for TTD in FACT-G total, TOI, FAPSI-6, FWB, PWB, and PCS scores between groups. A numerically lower proportion of pts receiving pembro + docetaxel (39.9%) had improved + stable FACT-P total scores compared with placebo + docetaxel (45.3%). FACT-P and BPI-SF scores were generally maintained across all evaluated time points up to wk 81. Conclusions: HRQoL and disease-related symptom scores at all analyzed time points, as well as TTD and TTPP, were similar between the 2 trial arms. These data suggest that pembro + docetaxel did not negatively impact QoL in pts with mCRPC treated with prior NHA. Clinical trial information: NCT03834506 . [Table: see text]

Abstract Background Until five years ago, the metastatic hormone-sensitive prostate cancer (mHSPC) treatment landscape was dominated by the use of androgen deprivation therapy (ADT) alone. However, novel hormonal agents (NHAs) and chemotherapy are now approved for male patients with mHSPC. This study aimed to understand the impact NHA approvals had on mHSPC real-world treatment patterns and to identify the key factors associated with NHA or chemotherapy (± ADT) usage vs ADT alone. Methods Data were collected from the Adelphi Prostate Cancer Disease Specific Programme (DSP)™, a point-in-time survey of physicians and their consulting patients conducted in the United States (US), five European countries (France, Germany, Italy, Spain, and the United Kingdom), and Japan between January and August 2020. Data were analysed using descriptive statistics for individual countries, regions, and all countries combined. Pairwise analyses were used to further investigate differences between treatment groups at global level. Results 336 physicians provided data on 1195 mHSPC patients. Globally, at data collection, the most common mHSPC regimen initiated first was ADT alone (47%), followed by NHAs (± ADT) (31%, of which 21% was abiraterone, 8% was enzalutamide, and 2% was apalutamide) and chemotherapy (± ADT) (19%). The highest rates of ADT alone usage were observed in Japan (78%) and Italy (66%), and the lowest in Spain (34%) and in the US (36%). Our results showed that clinical decision making was driven by patient fitness, compliance, tolerance of adverse events, and balance of impact on quality of life vs overall survival. Conclusions This real-world survey offered early insights into the evolving mHSPC treatment paradigm. It showed that in 2020, ADT alone remained the most common initial mHSPC therapy, suggesting that physicians may prefer using treatments which they are familiar and have experience with, despite clinical trial evidence of improved survival with NHAs or chemotherapy (± ADT) vs ADT alone. Results also indicated that physicians prescribed specific mHSPC treatments primarily based on the following criteria: patient preference, disease burden/severity, and the performance status and comorbidities of the patient. To fully appreciate the rapidly changing mHSPC treatment landscape and monitor NHA uptake, additional real-world studies are required.

Aim: To assess homologous recombination repair mutation (HRRm) testing patterns in metastatic castration-resistant prostate cancer. Methods: A point-in-time, international survey conducted January-August 2020. Results: Three-quarters of physicians (oncologists, urologists, specialist surgeons) globally reported access to genetic/genomic testing and just over half were HRRm testers. Surveyed physicians reported HRRm testing and positivity rates for 1913 patients, which were 18.1% and 33.7%, respectively. Of patients tested (n = 347), the most common HRR genes tested were BRCA (91.6%) and ATM (47.3%). Conclusion: Overall testing rates were low, with physicians mostly testing patients they considered higher risk. Increased awareness and education are needed to encourage broader testing, to understand familial risk and to identify patients with worse outcomes or those eligible for life-prolonging treatments.

Prostate cancer (PC) is the second most common cancer, and the fifth most common cause of cancer-related mortality among male patients, worldwide. In Europe and Japan, the incidence of PC in men in 2020 exceeded that of lung cancer. Although national and regional clinical guidelines for the treatment of metastatic castration-resistant prostate cancer (mCRPC) are available in Europe and Japan, a literature review did not identify a published comparison of differing guidelines, but identified a lack of studies reporting treatment patterns of approved mCRPC treatments in Europe and Japan in normal clinical practice. The objective of this real-world study was to compare national treatment guidelines and real-world treatment for mCRPC in Europe and Japan. Physician-reported demographics, clinical characteristics, and treatment data of patients with mCRPC were drawn from the Adelphi Prostate Cancer Disease Specific Programme™, conducted in five European countries and Japan (2020) and analysed descriptively. All current treatment guidelines recommended the use of novel hormonal agents (NHA—abiraterone/enzalutamide) and chemotherapy (mainly docetaxel), with some intercountry differences, with NHA rechallenge accepted in Germany, Italy and Japan, but not in France, Spain or the United Kingdom. Overall, 271 physicians provided data for 1753 patients. At 1st-line (1L), the most common treatment was NHAs followed by (→) chemotherapy, in all countries. Chemotherapy was the most common 2nd-line (2L) treatment, except in Japan, where 2L NHA use was preferred, and Spain, where both were used equally. NHA → chemotherapy and chemotherapy → NHA were the first and second usual 1L → 2L sequence in most countries, except for France, where the second most common sequence was NHA → NHA, and Japan, with androgen deprivation therapy alone → NHA. Real-world mCRPC treatment patterns largely reflected national guidelines. It is expected that guidelines and treatment patterns will change with the development of new treatment options.

Aim: To assess the patterns of genetic testing for homologous recombination repair mutations in patients with metastatic castration-resistant prostate cancer (mCRPC) pre-PARP inhibitors approval. Patients & methods: mCRPC patients were selected in an oncology electronic medical records database. Patterns and predictors of testing for ATM, BRCA1/2, CDK12, PALB2 and FANCA gene alterations were assessed. Results: Of 5213 mCRPC patients, 674 (13%) had a documented genetic test. The number of tested patients increased from 1 in 2013 to 313 in 2018 (out of 3161 and 3010 clinically active patients, respectively). Receiving care in an academic oncology center (versus a community-based center) strongly predicted genetic testing (hazard ratio = 2.41). Conclusion: The use of and access to genetic testing pre-PARP inhibitor approval was suboptimal. Lay abstract In 2017, US guidelines recommended the use of genetic testing in patients with metastatic castration-resistant prostate cancer (mCRPC). While the initial goal of genetic testing was to guide referral to genetic counselling and clinical trial enrollment, it is now also used to identify patients who could benefit from new drugs that target specific molecular defects. Using medical record data of US patients with mCRPC, we found that the rates of genetic testing and the breadth of molecular defects tested were suboptimal from 2013 to 2019. We also found lower rates of genetic testing in patients treated in community-based centers compared with those treated in academic oncology centers. These results underscore the importance of increasing the take up rate of genetic testing in patients with mCRPC to help guide treatment decisions.

This US retrospective study described treatment outcomes among patients with castration resistant prostate cancer receiving docetaxel following next generation hormonal agents in the metastatic setting from 2013-2019 (N = 5,213). Treatment duration with docetaxel in second/third-line was short ( similar to 4 months), and most patients died within one year. Results highlight a significant unmet need and serve as a benchmark for future studies. Background: Real-world evidence suggest that next generation hormonal agents (NHAs) abiraterone and enzalutamide were preferred as first-line (1L) therapies for metastatic castration-resistant prostate cancer (mCRPC) in the United States (US) pre-2020, with chemotherapies, particularly docetaxel, being preferred in subsequent lines (2L + ). This real-world study described patient characteristics, treatment patterns, time on treatment (ToT) and overall survival (OS) among patients with mCRPC treated with 2L and 3L docetaxel post-NHAs in the mCRPC setting. Methods: Adults with confirmed adenocarcinoma mCRPC diagnosis and >= 1 month of follow-up post-diagnosis were selected from a US electronic health record-derived oncology de-identified database (01/2013-03/2019). Based on the observed line of therapy sequences post-mCRPC diagnosis, patients who received NHA therapy in 1L and docetaxel therapy in 2L were included in the 2L docetaxel cohort, and patients who received NHA therapy in both 1L and 2L and docetaxel therapy in 3L were included in the 3L docetaxel cohort. ToT and OS were evaluated using Kaplan-Meier analysis. Results: Among 5,213 patients with mCRPC, 278 and 166 were included in the 2L and the 3L docetaxel cohorts, respectively (median age: 73 years for both cohorts). ADT was the most used class of medication pre-mCRPC ( > 75%). For the 2L cohort, the most common sequence post-mCRPC was 1L abiraterone -> 2L docetaxel (52.5%), while the median ToT and OS post-2L start were 4.1 and 10.5 months, respectively; for the 3L cohort, the most common sequence post-mCRPC was 1L abiraterone -> 2L enzalutamide -> 3L docetaxel (67.5%), while the median ToT and OS post-3L start were 3.8 and 8.7 months, respectively. Conclusions: This real-world study provides novel data on patients treated with docetaxel post-NHAs in a mCRPC setting and highlights the critical unmet need for developing more effective treatment options in this population.

Therapeutic options for metastatic castration-resistant prostate cancer (mCRPC) patients are continuously advancing. We described mCRPC treatment patterns in the US from 2013 to 2019. Patients with a confirmed mCRPC diagnosis and adenocarcinoma histology were included in the US Flatiron Health Electronic Health Record-derived de-identified database. Treatment patterns [including treatment per lines of therapies (LOTs), LOT sequences, and time on treatment] and overall survival (OS) have been described in mCRPC settings. Of 5213 patients (mean age: 72.6 years), 4374 (83.9%) were treated with ≥ 1 LOT post-mCRPC diagnosis (among those with ≥ 1 LOT, 55.3%, 29.5%, 14.7%, and 6.7% had ≥ 2, 3, 4, and 5 LOTs, respectively). In first line (1L), the main treatment class was next-generation hormonal agents (NHA; 62.5% of patients with ≥ 1 LOT), while the shortest and longest time on 1L were observed for chemotherapy (median 2.8 months) and NHA (median 5.1 months), respectively. The most common LOT sequences were NHA → NHA (29.4% of patients with ≥ 2 LOTs) and NHA → NHA → chemotherapy (16.7% of patients with ≥ 3 LOTs). In Kaplan–Meier analyses, the median OS was 19.4, 14.6, and 11.1 months post-1L, 2L, and 3L start, respectively. Patients who moved rapidly through LOTs had an increased risk of death. NHA were widely used as 1L therapy in mCRPC patients from 2013 to 2019, but time on 1L NHA treatment was on average < 6 months. While NHA → NHA was the most observed 1L → 2L LOT sequence, a plethora of other LOT sequences were observed. OS was poor, highlighting an unmet need for life-prolonging treatments.

In oncology trials, treatment switching from the comparator to the experimental regimen is often allowed but may lead to underestimating overall survival (OS) of an experimental therapy. This study evaluates the impact of treatment switching from control to olaparib on OS using the final survival data from the PROfound study and compares validated adjustment methods to estimate the magnitude of OS benefit with olaparib. The primary population from PROfound (Cohort A) was included, alongside two populations approved for treatment with olaparib by the European Medicines Agency and US Food and Drug Administration: BRCAm and Cohort A+B (excluding the PPP2R2A gene). Five methods were explored to adjust for switching: excluding or censoring patients in the control arm who receive subsequent olaparib, Rank Preserving Structural Failure Time Model (RPSFTM), Inverse Probability of Censoring Weights, and Two-Stage Estimation. The RPSFTM was considered the most appropriate approach for PROfound as the results were robust to sensitivity analysis testing of the common treatment effect assumption. For Cohort A, the final OS hazard ratio reduced from 0.69 (95% CI 0.5–0.97) to between 0.42 (0.18–0.90) and 0.52 (0.31–1.00) for olaparib versus control, depending on the RPSFTM selected. Median OS reduced from 14.7 months to between 11.73 and 12.63 months for control. The magnitude of the statistically significant (P < 0.05) survival benefit of olaparib versus control observed in Cohort A of PROfound is likely to be underestimated if adjustment for treatment switching from control to olaparib is not conducted. The RPSFTM was considered the most plausible method, although further development and validation of robust methods to estimate the magnitude of impact of treatment switching is needed.

229 Background: The clinical journey of PC is evolving rapidly. New hormonal agents (NHA) have demonstrated clinical efficacy in metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castrate-resistant prostate cancer (nmCRPC) and metastatic castrate-resistant prostate cancer (mCRPC). A shift in the treatment landscape considering precision medicine, recently supported by the phase III PROFOUND study, suggests updates to the currently limited clinical guideline recommendations for genomic testing. Better understanding of the patient pathway and respective proportion of patients to support patient care is needed. The objective of this SLR was to summarize published literature on the prevalence of mHSPC, nmCRPC, mCRPC and HRR gene alterations. Methods: An SLR was conducted across nine databases in OVID to capture English language studies published 01/2009–05/2019 on global epidemiology and clinical practice trends for mHSPC, nmCRPC, mCRPC and HRRm. 4,732 papers were identified which were systematically screened for inclusion. Grey literature searches included 10 conference proceedings from 2014–2019. Results: In total, 244 observational publications met the inclusion criteria - 4 studies reported the prevalence of mCRPC, 3 on nmCRPC and 0 on mHSPC. From these, the estimated prevalence of mCRPC and nmCRPC is 1.6–2.1 and 1.1–2.1 per 100 PC cases, respectively. HRRm were investigated in 13 publications with next generation sequencing of tissue and blood samples being reported as the most frequent method. Of the HRR gene alterations examined, BRCA2 were found to have the highest prevalence with a range of 4.5–9.3 and 1.1–15.1 per 100 overall PC cases for germline and somatic gene alterations, respectively. Other prevalent HRR gene alterations included germline ATM, BRCA1 and CHEK2. Conclusions: Limited data are available evaluating the prevalence of mHSPC, nmCRPC and mCRPC required to quantify the burden of these populations suggesting a lag in the published literature following updates to US treatment guidelines. Our review also shows that HRR gene alterations, specifically BRCA2, are prevalent in PC consistent with recently published data on PROFOUND population.

Objective: The COMBI-AD trial demonstrated the efficacy and safety of dabrafenib and trametinib in combination vs placebo as adjuvant treatment of patients with BRAF V600E/K mutation-positive resected Stage IIIA (lymph node metastasis >1 mm), IIIB, or IIIC melanoma. This analysis evaluated the cost-effectiveness of dabrafenib and trametinib vs observation from a US healthcare payer perspective. Methods: This evaluation employed a non-homogeneous, semi-Markov, cohort model with health states for relapse-free survival (RFS), post-locoregional recurrence (LR), post-distant recurrence (DR) receiving first-line treatment, and post-DR receiving second-line treatment. A 50-year modeling time horizon was used. Transition probabilities were estimated based on individual patient data (IPD) from the COMBI-AD trial. Health-state utilities were estimated using EuroQol (EQ-5D) index values from COMBI-AD and published sources. Direct medical costs associated with treatment of melanoma were considered, including costs of BRAF mutation testing, medication and administration costs for adjuvant and metastatic treatments, costs of treating recurrence, and costs of adverse events. Costs and quality-adjusted life-years (QALYs) were discounted at 3.0% annually. Results: Compared with observation, adjuvant dabrafenib and trametinib was estimated to result in a gain of 2.15 QALYs at an incremental cost of $74,518. The incremental cost-effectiveness ratio (ICER) was estimated to be $34,689 per QALY. In deterministic sensitivity analyses, the ICER was sensitive to the cost of dabrafenib and trametinib and the distribution used for projecting RFS beyond the end of follow-up in the COMBI-AD trial. At a cost-effectiveness threshold of $100,000 per QALY, the probability that dabrafenib and trametinib is cost-effective was estimated to be 92%. Conclusions: Given generally-accepted cost-effectiveness threshold values in the US, dabrafenib plus trametinib is likely to be a cost-effective adjuvant therapy for patients with BRAF mutation positive melanoma. These results may be useful for policy-makers in their deliberations regarding reimbursement and access to this treatment.

BACKGROUND:Before the approval of dabrafenib and trametinib in combination, there were no approved therapies in the adjuvant setting that target the RAS/RAF/MEK/ERK pathway.OBJECTIVE:To evaluate the budget impact of dabrafenib and trametinib in combination for adjuvant treatment of patients with BRAF V600 mutation-positive resected Stage IIIA, IIIB, or IIIC melanoma from a U.S. commercial payer perspective using data from the COMBI-AD trial, as well as other sources.METHODS:The budget impact of dabrafenib and trametinib in combination for patients with BRAF V600E/K mutation-positive, resected Stage IIIA, IIIB, or IIIC melanoma was evaluated from the perspective of a hypothetical population of 1 million members with demographic characteristics consistent with those of a commercially insured U.S. insurance plan (i.e., adults aged less than 65 years) using an economic model developed in Microsoft Excel. The model compared melanoma-related health care costs over a 3-year projection period under 2 scenarios: (1) a reference scenario in which dabrafenib and trametinib are assumed to be unavailable for adjuvant therapy and (2) a new scenario in which the combination is assumed to be available. Treatments potentially displaced by dabrafenib and trametinib were assumed to include observation, high-dose interferon alpha-2b, ipilimumab, and nivolumab. Costs considered in the model include those of adjuvant therapies and treatment of locoregional and distant recurrences. The numbers of patients eligible for treatment with dabrafenib and trametinib were based on data from cancer registries, published sources, and assumptions. Treatment mixes under the reference and new scenarios were based on market research data, clinical expert opinion, and assumptions. Probabilities of recurrence and death were based on data from the COMBI-AD trial and an indirect treatment comparison. Medication costs were based on wholesale acquisition cost prices. Costs of distant recurrence were from a health insurance claims study.RESULTS:In a hypothetical population of 1 million commercially insured members, 48 patients were estimated to become eligible for treatment with dabrafenib and trametinib in combination over the 3-year projection period; in the new scenario, 10 patients were projected to receive such treatment. Cumulative costs of melanoma-related care were estimated to be $6.3 million in the reference scenario and $6.9 million in the new scenario. The budget impact of dabrafenib and trametinib in combination was an increase of $549 thousand overall and 1.5 cents per member per month.CONCLUSIONS:For a hypothetical U.S. commercial health plan of 1 million members, the budget impact of dabrafenib and trametinib in combination as adjuvant treatment for melanoma is likely to be relatively modest and within the range of published estimates for oncology therapies. These results may assist payers in making coverage decisions regarding the use of adjuvant dabrafenib and trametinib in melanoma.DISCLOSURES:Funding for this research was provided to Policy Analysis Inc. (PAI) by Novartis Pharmaceuticals. Stellato, Moynahan, and Delea are employed by PAI. Ndife, Koruth, Mishra, and Gunda are employed by Novartis. Ghate was employed by Novartis at the time of this study and is shareholder in Novartis, Provectus Biopharmaceuticals, and Mannkind Corporation. Gerbasi was employed by PAI at the time of this study and is currently an employee, and stockholder, of Sage Therapeutics. Delea reports grant funding from Merck and research funding from Amgen, Novartis, Sanofi, Seattle Genetics, Takeda, Jazz, EMD Serono, and 21st Century Oncology, unrelated to this work.

141 Background: Dabrafenib plus trametinib (D+T), ipilimumab plus nivolumab (I+N), and both nivolumab and pembrolizumab (“PD-1 mono”) are approved for the 1L treatment of MM. This study reports real world 1L TTNT for patients receiving these therapies by LDH status. Methods: This was a retrospective, observational study. MM patients initiating 1L treatment with D+T, I+N, or PD-1 monotherapy from Jan-2014 through Jun-2017 were identified from community oncology practices in the U.S. Patients treating oncologist abstracted patient date into case report forms. LDH at initiation of treatment was classified by the provider as normal or abnormal ( > 1x and < 2x ULN or ≥ 2x ULN) according to the reference laboratory. TTNT was calculated from 1L initiation to initiation of second-line (2L). Cox proportional hazard models estimated the risk of initiating 2L (proxy for progression) between groups adjusted for age, gender, brain/liver metastases (mets), number of mets and ECOG-PS. Results: Data for 332 patients were submitted by 53 providers including 51.6% who initiated 2L. Abnormal LDH: D+T = 60.3%, ipi/nivo = 53.0%, PD-1 mono = 35.4%. No differences in the frequency of patients with stage IV M1c, brain mets, ECOG, or discontinuation due to toxicity (8.4% of all patients) were noted between cohorts. TTNT was significantly longer in both normal and abnormal LDH cohorts for D+T (14.1 and 11.6 mo.) vs. ipi/nivo (10.1 and 10.2 mo.) but not PD-1 mono (13.3 and 10.6). Adjusted for confounding variables in the abnormal LDH cohort the hazard ratio (HR) for risk of 2L initiation was significantly higher (2.08, p < 0.01) for ipi/nivo vs. D+T but not significant different among normal LDH patients (HR = 1.89, p = 0.054). No significant difference in the risk of 2L initiation between D+T and ipi/nivo were noted in either the normal or abnormal cohorts. Conclusions: For normal and abnormal LDH cohorts 1L TTNT was longer for patients receiving D+T vs. ipi/nivo (but not vs. PD-1 mono). Using the multivariate model we observed the risk of 2L initiation, a proxy for progression, was higher for ipi/nivo treated vs. D+T adjusted for clinical factors for abnormal LDH patients.

Aim: Targeted therapy (TT) and immuno-oncology (IO) drugs are approved for patients with BRAF mutant metastatic melanoma (MM). We compared real-world outcomes for first-line (1L) TT versus 1L IO to evaluate optimal sequencing. Materials & methods: Physicians-identified BRAF mutant MM patients initiating 1L TT or IO therapies and extracted treatment, disease and clinical outcomes including disease response which were compared between TT and IO and individual regimens. Results: 440 MM patients (TT = 283, IO = 157) were identified. A higher proportion of TT patients had liver metastases (46.3 vs 35.0%) and abnormal lactate dehydrogenase (61.1 vs 42.7%). IO-treated had a RECIST-determined response rate of 45.9 versus 60.1% for TT and time on treatment of 7.2 versus 11.4 months, respectively. There was no survival difference between cohorts. Conclusion: Despite higher risk patients, 1L TT resulted in higher response rate and longer treatment duration suggesting a preferred 1L sequence.

Surgery is the mainstay treatment for operable nonmetastatic melanoma, but recurrences are common and limit patients’ survival. This study aimed to describe real-world patterns of treatment and recurrence in patients with melanoma and to quantify healthcare resource utilization (HRU) and costs associated with episodes of locoregional/distant recurrences. Adults with nonmetastatic melanoma who underwent melanoma lymph node surgery were identified from the Truven Health MarketScan database (1 January 2008 to 31 July 2017). Locoregional and distant recurrence(s) were identified on the basis of postsurgery recurrence indicators (i.e. initiation of new melanoma pharmacotherapy, new radiotherapy, or new surgery; secondary malignancy diagnoses). Of 6400 eligible patients, 219 (3.4%) initiated adjuvant therapy within 3 months of surgery, mostly with interferon α-2b (n=206/219, 94.1%). A total of 1191/6400 (18.6%) patients developed recurrence(s) over a median follow-up of 23.1 months (102/6400, 1.6% distant recurrences). Among the 219 patients initiated on adjuvant therapy, 73 (33.3%) experienced recurrences (distant recurrences: 13/219, 5.9%). The mean total all-cause healthcare cost was $2645 per patient per month (PPPM) during locoregional recurrence episodes and $12 940 PPPM during distant recurrence episodes. In the year after recurrence, HRU was particularly higher in patients with distant recurrence versus recurrence-free matched controls: by 9.2 inpatient admissions, 54.4 inpatient days, 8.8 emergency department admissions, and 185.9 outpatient visits (per 100 person-months), whereas all-cause healthcare costs were higher by $14 953 PPPM. It remains to be determined whether the new generation of adjuvant therapies, such as immune checkpoint inhibitors and targeted agents, will increase the use of adjuvant therapies, and reduce the risk of recurrences and associated HRU/cost.

Abstract Background: Incidence of stage III/regional melanoma by patient characteristics can help estimate the number of high-risk patients (pts) potentially eligible for adjuvant treatment in a rapidly evolving field and guide the design of future clinical trials based on real-world data. The study describes the incidence of AJCC7 stage III/regional melanoma in the US (a) over time and (b) by melanoma prognostic factors. Methods: Pts newly diagnosed with invasive melanoma were identified in the US Surveillance, Epidemiology, and End Results (SEER) cancer registry (years 2010 -2014; n = 106,195). Stage III melanoma was defined based on the AJCC7 classification (n = 7,669); pts classified as AJCC7 stages I/II but with reported evidence of lymphatic metastasis were considered regionally advanced and included (n =169). Annual incidence was defined as the proportion of individuals in the general population who developed stage III/regionally advanced melanoma over a one-year period (the denominator included the full or age/sex-specific population, as appropriate). Results: During the study period, 7,838 (7.4%) pts were diagnosed with stage III/regional melanoma . The incidence of invasive melanoma has increased from year 2010 to year 2014: from 14.16 to 16.15/100,000 for stages I-IV combined and from 1.25 to 1.50/100,000 for stage III/regional melanoma. Based on the 2014 incidence and the most recent age-specific census population data, it is estimated that 5,109 pts were newly diagnosed in year 2016 with stage III/regional melanoma. In 2014, the incidence of stage III/regional melanoma was higher in elderly than adults and children (incidence per 100,000: 5.16 vs 1.33 and 0.08, respectively) and in males than females (1.79 vs 1.23). Table 1 presents incidence estimates by melanoma characteristics. Conclusions: The results of this analysis indicate an increase in stage III/regional melanoma incidence from 2010 to 2014 and a high incidence of stage III melanoma with poor prognostic factors. Table 1.Stage III1/regional melanomaIncidence in year 20142 (estimate of newly diagnosed in the US in 20163) By tumor thickness4≤ 0.8 mm0.12/ 100,000 population (n=393)0.81 - 1mm0.04 / 100,000 population (n=143)1.01 - 2 mm0.31/ 100,000 population (n=1,028)2.01 - 4 mm0.29/ 100,000 population (n=990)> 4 mm0.37/ 100,000 population (n=1,270)By ulcerationYes0.54/ 100,000 population (n=1,858)No0.62/ 100,000 population (n=2,099)Unknown0.34/ 100,000 population (n=1,152)By number mitoses per square mmNone0.05/ 100,000 population (n=174)1 - 50.58/ 100,000 population (n=1,961)6 - 100.20/ 100,000 population (n=672)≥ 110.17/ 100,000 population (n=588)Unknown0.50/ 100,000 population (n=1,713)Any LN involvement1.40/ 100,000 population (n=4,725)1 LN0.78 / 100,000 population (n=2,622)2 - 3 LNs0.34 / 100,000 population (n=1,155)> 3 LNs0.16/ 100,000 population (n=531)Unknown number of LNs0.12/ 100,000 population (n=416)Microscopic nodal metastasis5 (regardless of the number of LNs)0.81/ 100,000 population (n=2,725)Satellite / in-transit without LN involvement 0.09/100,000 population (n=311)LN, lymph node; [1] Defined using the American Joint Committee on Cancer (AJCC) 7 edition classification. [2] New cases diagnosed in 2014 (most recent year available in SEER) / 100,000 population; based on mid-year general population in 2014 for the geographical areas covered by the SEER (118,955,244 individuals). [3] Based on age-specific incidence and most recent population estimates (year 2016) from the US Census Bureau (age < 21 years = 86,391,289; age 21- 64 years = 187,492,029; age > 64 years = 49,244,195). [4] "Unknown" not shown if incidence <0.05 /100,000 population. [5] Includes pts identified with clinically occult (microscopic) LN metastases only, pts with isolated tumor cells only in LN, and/or pts who underwent sentinel LN biopsy and were found to have LN metastasis. Citation Format: Ahmad M. Tarhini, Sameer R. Ghate, Antonio Nakasato, Raluca Ionescu-Ittu, Sherry Shi, Briana Ndife, Rebecca Burne, François Laliberté, Mei Sheng Duh. Incidence of AJCC7 stage III or regionally advanced cutaneous melanoma in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1203.

e21516 Background: Combination TT, dabrafenib/trametinib (D+T) or vemurafenib/cobimetinib (V+C) and combination I-O (ipilimumab/nivolumab [I+N]) or PDL1 monotherapy (nivolumab [N] or pembrolizumab [P]) are approved for the treatment of BRAF+ MM. Without head to head trials comparing TT and I-O comparative effectiveness of real world clinical outcomes may better inform treatment decisions. Methods: Physicians from the Cardinal Health Oncology Provider Extended Network identified BRAF+ MM patients initiating 1L with D+T, I+N, N or P after 01/01/2014 through 6/31/2017. Treatment and clinical data (including target lesion measurements) were entered into electronic case-report forms which were validated by clinical research staff. 1L ORR using RECIST v1.1 and TTF was compared between TT and I-O. Odds ratio (OR) for objective response (complete or partial) using multivariate logistic regression models and hazard ratio (HR) for TTF using a Cox proportional hazards model adjusted for patient characteristics was calculated. Results: 53 providers contributed 440 patients: TT = 283 (D+T = 188, V+C = 95), I-O = 157 (I+N = 86, N or P = 71). Patient characteristics, ORR, median TTF, and model estimates are in the table. ORR was significantly higher in TT v I-O (60.1% v 45.9%, p < 0.01); adjusted odds of objective response 42% less for I-O (OR = 0.58). Median TTF: TT = 11.4 v I-O = 7.1 (p < 0.001); adjusted risk of treatment failure increased by 64% for I-O treated compared to TT: HR: 1.64; 95% CI: 1.25-2.14, p < 0.001. Conclusions: In the largest community-based study of 1L outcomes for BRAF+ MM ORR was significantly higher for TT (unadjusted and adjusted) and TTF longer for TT v I-O. We observe an apparent preference for TT in the community in higher risk patients (liver metastases and LDH value). TT N = 283 I-O N = 157 Median Age (Yr) 61 61 Female (%) 40.6 41.4 LDH Normal (%) 36.4 51.6 Sites of Metastases (%) Lung 67.8 70.1 Liver* 46.3 35.0 Brain 9.9 9.6 ORR (%)* 60.1 45.9 Adjusted OR; 95% CI* REF 0.58; 0.36-0.94 Median TTF (mo)* 11.4; 10.2-13.1 7.2; 6.2-10.0 Adjusted HR: 95% CI* REF 1.64*; 1.25-2.14 * p < 0.05

e21574 Background: Adjuvant treatment options for stage III melanoma patients (pts) are increasing with the approval of new agents. Little has been reported about the real world treatment patterns in a modern patient population. This study evaluated clinical characteristics and treatment patterns in Stage III melanoma pts during the time when ipilimumab and interferon were the only FDA approved treatment options. Methods: A retrospective observational cohort study of pts diagnosed with stage III melanoma from 11/2015 to 03/2017, with follow-up through 09/2017 were analyzed. Data were obtained from The US Oncology Network/McKesson Specialty Health iKnowMed electronic health record (EHR) database. Demographics, clinical characteristics, and adjuvant treatment patterns were characterized. Results: 325 pts with stage III melanoma at diagnosis were identified. Patients were staged using AJCC 7th edition criteria. Median follow-up time was 11.4 months. 92 pts (28.3%) initiated adjuvant therapy (adj) while 233 (71.7%) were classified as watch and wait approach (WW), defined as no evidence of systemic treatment for 6 months post-diagnosis (p < 0.05). Overall, 34.2% of pts were stage IIIA (n = 111), 38.8% (n = 126) stage IIIB, 23.1% (n = 75) stage IIIC, and 4.0% (n = 13) stage III not otherwise specified (NOS). The proportion of pts who initiated adj by stage was 22.5%, 32.5%, 26.7%, and 46.2% for IIIA, IIIB, IIIC, and III NOS, respectively. Adj pts predominantly initiated ipilimumab (88.0%) versus interferon (12.0%) (p < 0.05). Median age was 60 years, (59 years adj vs. 61 WW, p = 0.17), and 58.8% were male (55.4% adj vs. 60.1% WW, p = 0.44). Most pts (91.4%) were Caucasian (91.3%, adj, 91.4% WW). Conclusions: The majority (71.7%) of pts with stage III melanoma were not treated with adj, regardless of substage. Understanding adjuvant treatment patterns among stage III melanoma pts is important as new treatment options become available for this population. Additional analyses to evaluate the impact of adj and WW on recurrence and survival are planned.