Precision medicine has afforded oncologists the opportunity to develop individualized approaches to treat nonsmall cell lung cancer (NSCLC), one of the most devastating malignant disorders, which until the past decade was thought to be invariably fatal within months. These advances are welcome, but rapid development of complex therapeutic options has led to confusion about how to choose the right drug at the right time for the right patient. Additionally, the simultaneous development and progress of immune checkpoint inhibitors (ICIs) has contributed to confusion in the choice of initial treatment options in the first-line setting for patients with dual expression of PD-L1 and driver mutations.

Next-generation sequencing (NGS) may clarify the treatment path in NSCLC by aiding assessment of the molecular status of the individual patient, leading to a personalized medicine approach. The following case study and literature review highlight the need for further research.

A 27-year-old student from India pursuing a doctoral degree in economics at the University of Oxford in the United Kingdom developed a progressive cough, shortness of breath, and weight loss in the spring of 2017. He visited his general practitioner at Oxford and was initially treated with a course of antibiotics (azithromycin), without much relief. He continued to lose weight and began to develop cachexia.

After 2 weeks of initial symptoms, a chest radiograph revealed bilateral multiple nodular lesions and a large 3.5 &times; 4 cm lesion in the right lung. The patient was started on antituberculosis treatment for several weeks with an empirical diagnosis of pulmonary tuberculosis. His condition continued to worsen. After 8 weeks of treatment, he developed hemoptysis and orthopnea. He was hospitalized in early June 2017. A PET/CT scan in June 2017 revealed a fluorodeoxyglucose (FDG)-avid, 40 &times; 35 mm (standard uptake value, 6) soft-tissue lesion in his right hilar and parahilar regions extending to the right middle lobe; multiple FDG-avid bilateral parenchymal lung nodules; bilateral mediastinal, hilar, and right supraclavicular nodes; and an FDG-avid lesion in the right adrenal gland suggestive of metastatic disease.

At this stage, the patient&rsquo;s right supraclavicular lymph node was biopsied, and the results revealed meta-static poorly differentiated adenocarcinoma, with 65% PD-L1 expression as determined by an NGS cancer panel (the National Health Service protocol for cancer panel, which included

). He needed 2 to 3 liters of oxygen continuously.

Given his worsening condition, the patient was airlifted to India to join his parents, with a diagnosis of terminal lung cancer and possible referral for comfort and hospice care. At this juncture, his family reached out to Carolina Blood and Cancer Care in Rock Hill, South Carolina, a Strategic Alliance Partner of Targeted Therapies in Oncology. Kashyap Patel, MD, CEO of Carolina Blood and Cancer Care, Rock Hill, SC, consulted remotely, providing guidance to the patient&rsquo;s oncologist in India throughout the course of the patient&rsquo;s treatment.

Pending a second opinion, his primary oncologist in India administered 1 cycle of pemetrexed, carboplatin, and bevacizumab (Avastin). The results of fluorescence in situ hybridization were positive for ALK.

We recommended starting the patient on alectinib (Alecensa) in August 2017.

Within 4 weeks of initiating treatment with alectinib, his performance status improved and he started walking with ambulatory oxygen. After 8 weeks of treatment, the patient started walking 1 mile daily and resumed his studies remotely.

His follow-up PET/CT scan in January 2018 revealed near complete resolution of all liver metastases and adrenal metastases. His lung lesions also resolved.

In December 2018, the patient completed the thesis for his doctoral degree and got married. In March 2019, his scans confirmed no evidence of disease. Apart from mild elevation of his liver function, all blood work results were also negative. He currently runs 3 to 4 kilometers every day, works full-time in India, and is enjoying married life. At the last assessment in the summer of 2019, he continued to feel well.

More than 228,000 people in the United States will be given a diagnosis of lung cancer1 in 2019. Lung cancer accounts for 13% of all new cancer cases and almost 25% of all cancer deaths.

It is the leading cause of cancer death regardless of gender or ethnicity. More than half of patients with lung cancer die within 1 year of receiving a diagnosis.

The 5-year survival rate is 19% for all stages, for stage IIIB and IV the rate is 6%.

Lung cancer is a complex group of disorders associated with a tremendous number of pos-sible molecular aberrations. The growth of many subtypes of lung cancer is driven by complex molecular changes and different abnormal molecular cell signaling pathways, which are often triggered by driver mutations. With these complex molecular subtypes, assessing, treating, and understanding lung cancer necessitates rapid evolution of clinical trials, targeted therapy development, and application of personalized medicine.

Targeted therapies and immuno-oncology (IO) agents play an important role in the treatment of advanced NSCLC. The use of IO agents combined with chemotherapy has revolutionized treatment and outcomes in many patients with advanced NSCLC. However, in patients with coexpression of PD-L1 and other driver mutations (in genes such as

), outcomes with IO agents have been disappointing.6 In particular, KEYNOTE-024 and KEYNOTE-021 excluded patients with sensitizing mutations in the

The only study of an ICI that included patients with

mutations and PD-L1 expression was stopped prematurely because of lack of efficacy.

It is reasonable to conclude that there is a lack of evidence related to clinical benefit from ICIs as a first-line treatment in patients with metastatic

-mutant NSCLC. Turnaround for PD-L1 testing is quick, but it may take longer to identify other driver mutations. It is prudent to check for all biomarkers prior to rushing to treatment with IO agents. It is reported that 1 of every 3 patients with

mutations may also express PD-L1; hence, it is important to check for all biomarkers prior to initiating immunotherapy. National Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing of 4 genes with targetable alterations (ie, with corresponding FDA-approved targeted therapies)

rearrangementsfor all patients with NSCLC. Additionally, the NCCN guidelines suggest consideration of testing other &ldquo;emerging&rdquo; biomarkers for rarer oncogenic drivers associated with targeted treatments; these include alterations in

NCCN also recommends the use of anti-EGFR monotherapy as first-line treatment for patients with EGFR-mutated NSCLC.

In a study of 1203 patients with advanced NSCLC treated in a community setting in 2017 and 2018, only 22% of patients underwent genotyping for all 4 NCCN-recommended genes, with testing rates for individual genes ranging from 29% (

).10 This study also revealed that only 45% of patients who may have qualified for FDA-approved targeted therapy had evidence of receiving targeted therapy. Furthermore, 37% of patients with a mutation in

and no evidence of progression on the corresponding tyrosine kinase inhibitor received an IO agent, although most of these patients were known to have the targeted alteration at the time of IO agent initiation. There is a significant knowledge gap concerning the need for biomarker testing. Lack of appropriate testing affects over 50% of patients with stage IIIB or IV lung cancer, and their outcome is adversely affected as targeted therapies are not offered despite being clinically indicated.

We present the above case study to emphasize the importance of genetic testing in patients with NSCLC. This case involved the application of clinical and practical experience, as well as the use of biomarker testing and NGS, and it demonstrates how these advanced technologies have increased therapeutic options for patients with NSCLC.

In summary, the field of mutation-directed precision medicine holds the greatest promise for achieving better survival rates while also reducing treatment adverse effects in patients with NSCLC. We are at the cusp of a paradigm shift, with scientific discoveries offering optimism and hope even for patients with stage IV NSCLC, who were once destined for limited survival rates and short life expectancies.

Key statistics for lung cancer. American Cancer Society website.

cancer.org/content/cancer/en/cancer/lung-cancer/about/key-statistics.html

. Updated October 1, 2019. Accessed October 28, 2019.

Cancer facts & figures 2019. American Cancer Society website.

cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf

How serious is lung cancer? American Lung Association website.

Lung cancer  non&ndash;small cell: statistics. Cancer.net website. &nbsp;

Lung Cancer Survival Rates. American Cancer Society website.

Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis.

. 2016;22(18):4585-4593. doi: 10.1158/1078-0432.CCR-15-3101.

Reck M, Rodr&iacute;guez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1positive non&ndash;small-cell lung cancer.

. 2016;375(19):1823-1833. doi: 10.1056/NEJMoa1606774.

Langer CJ, Gadgeel SM, Borghaei H, et al; KEYNOTE-021 Investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study.

. 2016;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3.

NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer, version 7. National Comprehensive Cancer Network website.

nccn.org/professionals/physician_gls/pdf/nscl.pdf

. Published August 30, 2019. Accessed October 21, 2019.

Gierman HJ, Goldfarb S, Labrador M, et al. Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices.

Articles

Clinical Articles

Precision medicine has afforded oncologists the opportunity to develop individualized approaches to treat non&ndash;small cell lung cancer, one of the most devastating malignant disorders, which until the past decade was thought to be invariably fatal within months.

Next-Generation Sequencing Can Improve Treatment Decisions, But Community Uptake Remains Delayed

Building upon the initial successes of antiPD-1 and anti&ndash;CTLA-4 therapies has been a major focus of drug development over the past several yearsbasically, in search of other agents that could generate &ldquo;immune-synergy.&rdquo; What the term means and implies is critically important: It refers to drugs that work better together than alone (or in sequence) through their individual mechanisms of action to enhance the host immune-response to cancer.

Ever since the first studies of checkpoint inhibitors were reported, we&rsquo;ve been on an exhaustive search to find the best partners for PD-1 and CTLA-4 antibodies to get more tumors to respond to the immune system. One of the most intriguing approaches involves the notion of generating an &ldquo;in vivo vaccine.&rdquo; Initial approaches included focused high-dose and hypofractionated radiation therapy at 1 or a few sites of metastatic disease given concurrently with systemic immunotherapy. In this scenario, the radiation induces &ldquo;immunogenic&rdquo; cell death, which is a unique dying process of the cancer cell in which the tumor releases otherwise hidden mutated proteins into the microenvironment. These proteins are then recognized and taken up by antigen-presenting cells, which subsequently instruct T cells to attack the cancer. This critical step of antigen recognition is requisite for the activation of the host immune system against cancer. Anecdotal observations showed that radiation could improve responses to checkpoint inhibitor therapy, and they have served as the basis for subsequent larger studies testing the addition of radiation to systemic immunotherapy.

Of particular interest at this year&rsquo;s European Society for Medical Oncology 2019 Congress were data from EV-103, a phase I trial of the checkpoint inhibitor pembrolizumab (Keytruda) combined with the novel antibody-drug conjugate (ADC) enfortumab vedotin (EV) in advanced bladder cancer (see pages 37-38).

We&rsquo;ve speculated that chemotherapy could similarly induce immunogenic cell death but the data were not compelling, probably because chemotherapy regimens are highly varied with the type and delivery of the agent. EV targets nectin-4, which is a cell-surface protein highly overexpressed in virtually 100% of urothelial cancers, and the attached payload is a highly potent microtubule disrupting agent called monomethyl aurostatin-E (MMAE).

In EV-103, the objective response rate for the combination in 45 patients was an eye-popping 71%, and 93% of patients had at least some decrease in tumor size.

I have personal experience in treating patients with EV early on, and along with others, I have speculated that EV had immunologic properties that made it an attractive partner to pair with antiPD-1 therapies. I think these data are compelling, to say the least, and have broad implications beyond just urothelial cancer if proven to be valid. For instance, one could envision developing similar ADCs with MMAE as a payload but targeting a variety of different cell-surface proteins unique for different cancer types, if in fact it is MMAE that induces the immunogenic cell death that we&rsquo;ve been coveting so much. The technology of ADC development has made significant strides in the last few years and I&rsquo;m excited to see what the future holds.

Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma.

2012;366(10):925-931. doi: 10.1056/NEJMoa1112824.

Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.

2018;379(24):2342-2350. doi: 10.1056/NEJMoa1809697.

Hoimes CJ, Rosenberg JE, Srinivas S, et al. EV-103: initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.

2019;30(Suppl 5; abstr 901O). doi: 10.1093/annonc/mdz249.

Building upon the initial successes of anti&ndash;PD-1 and anti&ndash;CTLA-4 therapies has been a major focus of drug development over the past several years&mdash;basically, in search of other agents that could generate &ldquo;immune-synergy.&rdquo; What the term means and implies is critically important: It refers to drugs that work better together than alone (or in sequence) through their individual mechanisms of action to enhance the host immune-response to cancer.

Synergism of Immune Checkpoint Inhibitors and Antibody-Drug Conjugates Induce Promising Response Rates

alterations in intrahepatic cholangiocarcinoma, investigators have identified it as a potential prognostic indicator of survival and a rational target of systemic cancer therapies.

Beyond the established frontline therapy of gemcitabine and cisplatin, patients with metastatic cholangiocarcinoma have limited options.1 &ldquo;For patients with advanced disease, we only have 1 established chemotherapy [that] allows a median overall survival [OS] of around 1 year,&rdquo; said Arndt Vogel, MD, PhD, professor of gastrointestinal oncology at Hannover Medical School in Germany during a presentation at the European Society for Medical Oncology (ESMO) 2019 Congress. &ldquo;Second-line therapy is not well established.&rdquo;

FGFR fusions are present in up to 15% of cases of intrahepatic cholangiocarcinoma and represent an emerging biomarker for therapy. Several presentations at the conference focused on outcomes related to aberrations in this gene and therapies that may be effective as targeted agents.

Findings from the prospective, observational PRELUDE study by Masafumi Ikeda, MD, and colleagues presented during the meeting showed that certain patient characteristicssuch as age <65 years (

= .023), and hepatitis B or C positive status (

fusionpositive intrahepatic and perihilar cholangiocarcinoma. The results also showed that

fusions were present in 7.7% of patients with intrahepatic cholangiocarcinoma.

A presentation by Daniel R. Almquist, MD, and colleagues showed that somatic FGFR2 fusions may be a prognostic indicator for survival and chemotherapy response. In a cohort of 135 patients with intrahepatic cholangiocarcinoma, the investigators identified 45 that harbored FGFR2 fusions. Similar to the PRELUDE findings, the results showed an association with younger age, though it was not statistically significant. However, there was a greater likelihood for patients with these aberrations to have advanced disease stage IIIb or greater.

Efficacy with gemcitabine-platinum chemotherapy was also evaluated in both patient subgroups showing no significant difference in progression-free survival (PFS; HR, 1.19;

= .36). However, patients harboring FGFR2 fusions had significant improvements in median OS at 2.7 years versus 1.3 years in patients with no such aberration (HR, 0.44;

&ldquo;FGFR is a therapeutic target of interest, where future prospective studies will be necessary to validate the predictive, prognostic utility and its relevance in patient outcomes in intrahepatic cholangiocarcinoma,&rdquo; Almquist et al, wrote in their study.

The open-label, single-arm phase II FIGHT-202 trial was undertaken in the United States, Europe, Middle East, and Asia to evaluate the efficacy of pemigatinib, a selective oral inhibitor of FGFR1/2/3, in patients with locally advanced or metastatic cholangiocarcinoma despite at least 1 line of prior therapy. All patients had their

status centrally confirmed and were required to have adequate renal function. Patients in 3 cohorts were treated with oral pemigatinib at 13.5 mg daily using a 2-weeks-on/ 1-week-off schedule (FIGURE).

Results were presented at the ESMO 2019 Congress and showed that treatment with pemigatinib in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an

rearrangement or fusion induced an objective response rate (ORR) of 35.5%.

More than one-third of 107 total patients with

fusions/rearrangements (cohort A) responded to therapy, and the median duration of response (DOR) was 7.5 months (95% CI, 5.7-14.5). In contrast, there were no responses observed in the 20 patients enrolled with other

genetic alterations (cohort B) or the 18 with no

The higher ORR translated to a longer median PFS in cohort A. Median PFS was 6.9 months (95% CI, 6.2-9.6) in cohort A compared with 2.1 months (95% CI, 1.2-4.9) in B and 1.7 months (95% CI, 1.3-1.8) in C.

OS data in cohort A were not yet mature at the time of data cutoff (March 22, 2019), but with a median duration of follow-up of 15.4 months and a median duration of treatment of 7.2 months, the median OS was 21.1 months (95% CI, 14.8-not evaluable) in the cohort with

fusions/rearrangements. Median OS was 6.7 months (95% CI, 2.1-10.6) in cohort B after a median follow-up of 19.9 months and median duration of treatment of 1.4 months. In cohort C, the median OS was just 4.0 months (95% CI, 2.3-6.5) after a median follow-up of 24.2 months and median duration of treatment of 1.3 months.

&ldquo;Overall, I think these data indicate that FGFR inhibition is a meaningful treatment for this genetically defined subgroup of patients with cholangiocarcinoma,&rdquo; said Vogel, who is the lead investigator on the trial.

The study was not designed to make statistical comparisons between the 3 study cohorts. The primary end point was the confirmed ORR in cohort A by independent central review.

status and 85 with results available were considered for the trial. In total, 127 patients with

genetic alterations were included in cohorts A and B. The median age for the entire 146-patient cohort was 59 years (range, 26-78), but those in cohort A tended to be younger, Vogel said. Of those in cohort A, 70% were <65 years compared with 50% in B and 39% in C. Women represented 58% of patients, with 61% in cohort A, 55% in B, and 44% in C. Patients from North America accounted for 61% of the total cohort, 24% were from Western Europe, and 15% were from elsewhere in the world.

Among the 107 patients in cohort A, 92 fusions and 15 rearrangements were discovered. A total of 56 unique fusion partners were identified; the most common was BICC1, which occurred in 29% of patiemts. Forty-two partners were unique to a single patient, and no fusion partner was identified in >5%. &ldquo;We need a fusion partner agnostic test to find those patients,&rdquo; Vogel said.

In cohort A, the 35.5% ORR consisted of 3 complete responses (2.8%), 35 partial responses (32.7%), and 50 patients with stable disease (46.7%), for a disease control rate (DCR) of 82%. The ORR was consistent across subgroups.

Adverse events (AEs) were manageable and consistent with the mechanism of action of pemigatinib. The most common AE was hyperphosphatemia, which occurred in 60% of patients, but no grade &ge;3 cases were encountered. Hyperphosphatemia was managed with a low-phosphate diet, phosphate binders, diuretics, or dose reduction or interruptions. Just 3 patients required dose reductions/interruptions due to hyperphosphatemia.

Hypophosphatemia of any grade occurred in 23% of patients and was the most common grade &ge;3 AE, with a rate of 12%. No case of hypophosphatemia was clinically significant, and none led to treatment discontinuation or dose reduction.

Serous retinal detachment occurred in 4% of patients. &ldquo;[It] usually resolved spontaneously or after dose interruption,&rdquo; Vogel said.

Nine percent of patients discontinued due to AEs; the most frequent causes were intestinal obstruction and acute kidney injury (2 each).

Treatment was discontinued in all patients in cohorts B and C and in 76 of 107 patients in cohort A. Progressive disease led to discontinuation in 57 patients in cohort A, 15 in B, and 12 in C; discontinuations due to AEs occurred in 4 patients in cohort A and 2 each in cohorts B and C.

Dose reduction due to AEs was required in 14%, with the most common reasons being stomatitis (n = 5), palmar-plantar erythrodysesthesia syndrome (n = 5), arthralgia (n = 5), asthenia (n = 2), and onychomadesis (n = 2). Some 42% of patients required dose interruptions due to AEs.

Ongoing Phase III Studies of FGFR Inhibitors

Based on the data from FIGHT-202, the phase III FIGHT-302 study of pemigatinib compared with gemcitabine plus cisplatin in the first-line setting in patients with cholangiocarcinoma and FGFR2 fusions/rearrangements is ongoing (NCT03656536), Vogel said. The primary end point is PFS, with secondary end points including ORR, OS, DOR, DCR, and safety.

Another ongoing phase III trial, PROOF, is examining the adenosine triphosphatecompetitive, FGFR1/2/3 selection oral tyrosine kinase inhibitor infigratinib versus gemcitabine plus cisplatin in patients with FGFR2 gene fusions or translocations and cholangiocarcinoma in the frontline setting (NCT03773302). The primary end point is PFS, with secondary end points including ORR, OS, DOR, DCR, and safety.

Audrey Sternberg contributed to this article.

Sohal DPS, Shrotriya S, Abazeed M, Cruise M, Khorana A. Molecular characteristics of biliary tract cancer.

2016;107:111- 118. doi: 10.1016/j.critrevonc.2016.08.013.

Ikeda M, Maruki Y, Ueno M, et al. Frequency and clinicopathological characteristics of biliary tract carcinomas harboring the FGFR2fusion gene: a prospective observational study (PRELUDE study).

2019;30(suppl 5;abstr 723P). doi: 10.1093/annonc/mdz247.050.

Almquist DR, Javle M, Ciombor KK, et al. FGFR2 fusions and its effect of patient (pt) outcomes in intrahepatic cholangiocarcinoma (iCCA).

2019;30(suppl 5;abstr 726P). doi: 10.1093/annonc/mdz247.053.

Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA).

2019;30(suppl 5;abstr LBA40). doi: 10.1093/annonc/mdz394.031.

Abou-Alfa GK, Borbath I, Clarke SJ, et al. Infigratinib versus gemcitabine plus cisplatin multicenter, open-label, randomized, phase 3 study in patients with advanced cholangiocarcinoma with FGFR2 gene fusions/translocations: the PROOF trial.

2019;30(suppl 5;abstr 832TiP). doi: 10.1093/annonc/mdz247.158.

Given the frequency of <em>FGFR2</em>&nbsp;alterations in intrahepatic cholangiocarcinoma, investigators have identified it as a potential prognostic indicator of survival and a rational target of systemic cancer therapies.

FGFR2 Emerges as a Promising Target in Cholangiocarcinoma

Timothy A. Yap, MBBS, PhD, MRCP(UK), BSc(Hons)

The early development of PARP inhibitors in 2003 focused on their use in combination with cytotoxic chemotherapy agents, but this was eventually abandoned because of excess toxicity. Approximately 2 years later, data emerged showing synthetic lethality between PARP inhibitors and

mutations in ovarian cancer, leading the way to treatment of

Investigators have since determined that PARP inhibitors are active across a range of tumor types harboring

mutations and can also evoke responses in subsets of

According to Timothy A. Yap, MBBS, PhD, MRCP(UK), BSc(Hons), associate professor in the Department of Investigational Cancer Therapeutics and associate director of translational research at the Khalifa Institute for Personalized Cancer Therapy, both at The University of Texas MD Anderson Cancer Center in Houston, PARP inhibitors show synthetic lethality when combined with germline abnormalities in many DNA damage response (DDR) pathway components, such as mutations in the

genes. Some of these mutations may eventually be shown to &ldquo;predict robustly for antitumor response,&rdquo; he said.

Yap, who is also medical director of the Institute for Applied Cancer Science at MD Anderson, is investigating whether PARP inhibitors demonstrate similar synthetic lethality when combined with other targeted DDR therapies or different classes of anticancer drugs. He said he is particularly excited about efforts to combine PARP inhibitors &ldquo;with immunotherapies such as PD-1 or PD-L1 inhibitors, other DDR agents such as ATR inhibitors, and other molecularly targeted agents that may be used to induce a state of chemical &lsquo;BRCAness&rsquo; in HR [homologous recombination]proficient cancers, such as antiangiogenic agents.&rdquo; Yap said studies have already provided &ldquo;promising early results with rational combinations and responses beyond

The FDA has approved 4 PARP inhibitors as single-agent therapies for breast or ovarian cancer (TABLE 1): olaparib (Lynparza), rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna).

PARP inhibitors are a family of enzymes essential for many cellular processes in addition to DNA repair, including chromatin remodeling, transcription, messenger RNA processing, and replication fork stabilization.

PARP inhibitors primarily target the PARP1 and PARP2 isoforms, which detect and promote repair of DNA single- or double-strand breaks (DSBs) to maintain genomic stability.

Tumors harboring DDR pathway aberrations that prevent homologous recombination repair of DSBs depend on PARP to repair single-strand DNA breaks and prevent them from progressing to irreparable, synthetically lethal DSBs.

Investigators are still elucidating the complex mechanisms of PARP inhibitors, but, in addition to inhibiting PARP catalytic activity, these agents are known to trap PARP at sites of damaged DNA. The resulting PARP-DNA complexes are highly efficient at preventing DNA repair, resulting in greater accumulation of DSBs; replication fork collapse; and, ultimately, cell death.

&ldquo;The antitumor efficacy of the PARP-trapping PARP inhibitors is probably not dissimilar,&rdquo; Yap said. Veliparib, an investigational PARP inhibitor in late-stage clinical trial development, appears to be a weak PARP trapper, which may explain its less robust single-agent activity in preclinical trials.

Yap noted that PARP inhibitors mainly differ in their toxicities: &ldquo;For example, alopecia with talazoparib, transient elevations in liver transaminases with rucaparib, and hypertension with niraparib.&rdquo;

Despite recent treatment advances, metastatic castration-resistant prostate cancer (mCRPC) remains incurable.

An estimated 20% to 25% of men with metastatic prostate cancer harbor a homologous recombination pathway mutation,10 and 1 study found that 11% of prostate cancer specimens had pathogenic

Homologous recombination deficiency (HRD) mutations are associated with more aggressive disease and worse prognosis.13 Ongoing clinical trials are exploring PARP inhibitors as monotherapy or in combination with other therapies for prostate cancer (TABLE 2).

Several trials have evaluated single-agent olaparib in mCRPC featuring a DDR alteration, and findings suggest that olaparib is more active in patients with

mutations than in those with mutations in other DDR genes, such as

The open-label phase III PROfound trial (NCT02987543) enrolled 245 patients with

mutations (cohort A) and 142 with other DDR mutations (cohort B) whose dis- ease had progressed after abiraterone acetate (Zytiga) or enzalutamide (Xtandi).33 Patients were randomly assigned 2:1 to olaparib or physician&rsquo;s choice of enzalutamide or abiraterone.

Preliminary data presented at the European Society for Medical Oncology (ESMO) 2019 Congress associated olaparib with significant improvement in 12-month progression-free survival (PFS) compared with treatment of physician&rsquo;s choice (TPC) in cohort A (7.39 vs 3.55 months, respectively; HR, 0.34; 95% CI, 0.25-0.47;

In cohort A, olaparib also produced significant improvements in objective response rate (ORR) and median time to pain progression. Although the overall survival (OS) data for cohort A showed a favorable trend, the difference did not achieve a predefined boundary for statistical significance, possibly because of the high crossover rate from the TPC arm.

Olaparib did not significantly improve outcomes in cohort B.

The most common treatment-related adverse events (TRAEs) in the olaparib cohort were anemia (46%), nausea (41%), decreased appetite (30%), and fatigue (26%).

Data from the phase II TOPARP-B trial (NCT01682772) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting confirmed the activity of olaparib in progressive mCRPC harboring a DDR mutation.

Patients were randomly assigned to 300 or 400 mg of olaparib twice daily. The overall response rate in the 400-mg group was 54% (95% CI, 39%-69%) compared with 37% (95% CI, 23%-53%) in the 300-mg group.

The highest ORRs occurred in patients with

mutations (80% and 57%, respectively). Overall median PFS was 5.4 months.

The ongoing phase II open-label Galahad trial (NCT02854436) is assessing niraparib in patients with previously treated mCRPC and a DDR mutation, approximately half of whom have a

An interim analysis showed that pronounced clinical activity was largely confined to the

cohort, which had an ORR of 41%, a composite response rate of 63%, and median radiographic PFS (rPFS) of 8.2 months.

Common grade 3/4 TRAEs were anemia (29%), thrombo- cytopenia (15%), and neutropenia (7%).

In 2018, rucaparib received breakthrough therapy designation for

-mutated mCRPC based on promising efficacy in the phase II TRITON2 trial (NCT02952534).

Updated data presented at ESMO 2019 Congress confirmed rucaparib&rsquo;s activity.

mutation, the prostate-specific antigen response rate was 52% and the ORR was 44%, with a 5% complete response (CR) rate.

Responses were durable, persisting &ge;24 weeks in 60% of patients. Common grade &ge;3 TRAEs included anemia (11%) and asthenia/ fatigue (7%).

The phase III TRITON3 trial (NCT02975934) will compare rucaparib with TPC in progressive mCRPC with a

The phase III TALAPRO-2 trial (NCT03395197) is evaluating talazoparib with enzalutamide in unselected patients with mCRPC.

Preliminary data indicated promising activity and a manageable safety profile. Interim results from an ongoing phase I/II study of olaparib plus the PD-L1 inhibitor durvalumab (Imfinzi) in mCRPC also showed promising activity, particularly in patients with a DDR alteration.

Other combination trials are QUEST (NCT03431350), which is evaluating niraparib plus a novel antiPD-1 monoclonal antibody13; MAGNITUDE (NCT03748641), which combines niraparib with abiraterone and prednisone

; and PROPEL (NCT03732820), which is investigating first-line therapy with olaparib plus abiraterone.

Between 4% and 7% of patients with pancreatic cancer have a germline

mutation. Treatment options after progression of advanced pancreatic ductal adenocarcinoma (PDAC) are limited, and the presence of homologous recombination defects provides a rationale for evaluating PARP inhibitors in this disease.

Interim results from the phase III POLO trial (NCT02184195) suggest that olaparib holds promise as a maintenance therapy for patients with metastatic PDAC who have a germline

mutation and no progression after platinum-based chemotherapy.

At data cutoff, median PFS was significantly longer in patients randomly assigned to olaparib versus those given placebo (7.4 vs 3.8 months; HR, 0.53; 95% CI, 0.35-0.82;

= .004).40 However, the ORR, median OS, and health-related quality of life were not significantly different between the 2 arms.

Approximately one-fourth of patients treated with olaparib experienced a serious adverse event (AE).

Although the phase II RUCAPANC trial (NCT02042378) of rucaparib monotherapy for previously treated advanced PDAC harboring a

mutation was terminated early because of poor response, investigators noted that the 16% of patients who responded had durable, clinically significant responses.

Efficacy was enhanced in platinum-sensitive patients.

A recent interim analysis of a phase II trial (NCT03140670) of maintenance rucaparib showed greater success in platinum-sensitive patients with advanced PDAC and a

The ORR for the 19 evaluable patients was 37%, which included 6 partial responses (PRs) and 1 CR. Responses were confined to patients with a

mutation. The disease control rate (DCR) was 90% for &ge;8 weeks, and median PFS was 9.1 months.

Common AEs possibly related to treatment were nausea, dysgeusia, and fatigue.

An ongoing phase I dose-escalation trial (NCT01286987) is assessing the single-agent activity of talazoparib in advanced solid tumors that harbor a germline

Preliminary data for 13 patients with pancreatic cancer revealed an ORR of 20% (all PRs) and a clinical benefit rate of 30%.

Just 1 patient remained on talazoparib at data cutoff.

Final data from a phase II trial combining veliparib with FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy showed an ORR of 50%, median PFS of 7.2 months, and median OS of 11.1 months in patients with metastatic PDAC and a DDR mutation.

Outcomes were slightly better in platinum-na&iuml;ve patients with a family history of pancreatic cancer and a DDR mutation.

Additional trials are evaluating veliparib combined with gemcitabine and cisplatin (NCT01585805) and with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy (NCT02890355). In the phase II PARPVAX trial (NCT03404960), niraparib is being explored with an immune checkpoint inhibitor (nivolumab [Opdivo] or ipilimumab [Yervoy]) for advanced platinum-sensitive PDAC.

Immune checkpoint inhibitors have shown limited activity in pancreatic cancer, prompting investigators to look for synergistic combinations.

Olaparib and talazoparib are the only PARP inhibitors approved for breast cancer.

Although the single-agent activity of PARP inhibitors in BRCA1/2-mutated breast cancer is well established, interest in expanding their use to other settings is burgeoning (TABLE 2).

Regulatory approval of olaparib for germline

-mutated, HER2-negative metastatic breast cancer (mBC) was based on results of the randomized phase III OlympiAD trial, showing significant improvement in median PFS with olaparib versus physician&rsquo;s choice of chemotherapy (7.0 vs 4.2 months, respectively; HR, 0.58; 95% CI, 0.43-0.80;

Follow-up data showed no significant improvement in OS with olaparib, however.46 The randomized phase III OlympiA trial (NCT02032823) is assessing single-agent olaparib as adjuvant therapy in high-risk

-mutated, HER2-negative nonmetastatic breast cancer.

Talazoparib received FDA approval based on conclusions from the randomized phase III EMBRACA trial, which compared talazoparib with TPC in BRCA1/2-mutated advanced breast cancer.48 Median PFS was significantly longer in the talazoparib arm versus the TPC arm (8.6 vs 5.6 months; HR, 0.54; 95% CI, 0.41-0.71;

<.001), but median OS did not differ significantly between the groups.

Subsequently, a small trial suggested that neoadjuvant talazoparib could reduce tumor volume in early-stage breast cancer, leading to a larger trial (NCT03499353) to investigate the regimen&rsquo;s efficacy in triple-negative breast cancer (TNBC) with a germline

Talazoparib has also been studied in platinum-sensitive advanced HER2-negative breast cancer with homologous recombination pathway alterations besides

, producing an ORR of 25% in 12 evaluable patients.

Although the phase III BRAVO trial assessing single-agent niraparib in locally advanced or metastatic, HER2-negative,

-mutated breast cancer ended prematurely because of poor patient adherence,

ongoing studies continue to evaluate niraparib for breast cancer. The phase II ABC Study (NCT02826512) is testing niraparib in advanced, locally recurrent, BRCA-like, HER2-negative breast cancer, and a phase I trial (NCT03329937) is evaluating neoadjuvant niraparib in a similar population.

In the MEDIOLA trial (NCT02734004), olaparib was administered with durvalumab to women with germline

The ORR was 63%, median PFS was 8.2 months, and median OS was 20.5 months. The same combination is being studied in another phase II trial (NCT03801369) but for metastatic BRCA wild-type TNBC.

The ongoing VIOLETTE trial (NCT03330847) is combining olaparib with an investigational ATR inhibitor in previously treated advanced TNBC.

The phase II TOPACIO/KEYNOTE-162 trial (NCT02657889) investigated the combination of niraparib plus the antiPD-1 monoclonal antibody pembrolizumab (Keytruda).

The ORR was 21%, which included 5 CRs and 5 PRs, and the DCR was 49%.

- mutated tumors, producing an ORR of 47% and a DCR of 80%.

Common TRAEs were anemia (18%), thrombocytopenia (15%), and fatigue (7%); 15% of patients experienced immune-related AES.

The early development of PARP inhibitors in 2003 focused on their use in combination with cytotoxic chemotherapy agents, but this was eventually abandoned because of excess toxicity.

November 2 2019

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