Thao K . Huynh, PharmD , BCOP

Although chemotherapy is the mainstay of systemic treatment for advanced cholangiocarcinoma (CCA), there are limited treatment options when the disease progresses. Investigators are evaluating multiple studies that are focused on targeted therapies in this setting, and the results appear positive.

“This is a disease where every single day I feel we’re making meaningful progress, and it’s exciting to be part of this world right now because you can see the forward motion happening,” Rachna Shroff, MD, associate professor in the Department of Medicine, Division of Hematology and Oncology, and chief of gastrointestinal medical oncology at the University of Arizona Cancer Center in Tucson, said in an interview with T

Next-generation sequencing (NGS) has identified multiple targetable oncogenes in CCA. Approximately 45% of patients with intrahepatic cholangiocarcinoma (iCCA) have actionable genetic alterations with fibroblast growth factor receptor 2 (

) fusions or rearrangements occurring exclusively in iCCA.

“Cholangiocarcinoma is a very target-rich disease. From day 1, we need to understand the genetic landscape of this cancer [and patients should have NGS data],” Tanios S. Bekaii-Saab, MD, professor of medicine and consultant, Division of Hematology/ Oncology at Mayo Clinic in Phoenix, Arizona, said in an interview with 

FGF/FGFR is a signaling pathway responsible for regulating cell survival and mediating physiological functions. If the FGF/FGFR pathway is disrupted due to genetic alterations, malignancies may arise, including CCA.1 FGFR2 gene fusions or rearrangements are the most common oncogenic drivers in iCCA, accounting for approximately 13% of mutations.1,3 “Although this is a rare tumor with a rare subset, it [comprises] a meaningful percentage of patients in a disease that otherwise has very limited therapeutic options,” Shroff said.

Recently, the development of FGFR inhibitors has provided a promising class of agents in the treatment of CCA, especially since 

 fusion may not respond better to chemotherapy compared with 

 Results from a retrospective analysis demonstrated that survival outcomes in patients with iCCA harboring 

 fusions (n = 15) have similar median progression-free survival (PFS) compared with 

 wild type (n = 107), 6.2 months (95% CI, 2.0-16.8) versus 7.2 months (95% CI, 5.0-8.3) for firstline standard chemotherapy treatment, respectively.

 fusions and subsequent inhibition with targeted therapy [are] of great interest in cholangiocarcinoma primarily because we have multiple trials as proof of principle that we can effectively target this pathway,” Shroff said.

Three Agents in Development There are currently 3 FGFR inhibitors that treat CCA. Pemigatinib (Pemazyre) is the first FDA-approved agent for CCA based on results from the FIGHT-202 clinical trial (NCT02924376).

 FIGHT-202 is a phase 2, single-arm, multicenter, multicohort trial that evaluated the safety and efficacy of pemigatinib in previously treated, locally advanced, or metastatic CCA.5 In 107 patients evaluated with 

 fusions, the objective response rate (ORR) was 35.5% (95% CI, 26.5%-45.3%). The median duration of response (DOR) was 7.5 months (95% CI, 5.7-14.5) with disease control rate (DCR) of 82.2%. The median PFS was 6.9 months (95% CI, 6.2-9.6), and preliminary median OS was 21.1 months (95% CI, 14.8-not estimable).

Other FGFR inhibitors evaluated after progression on chemotherapy include infigratinib and futibatinib. Infigratinib was evaluated in advanced CCA in a single-arm, phase 2 trial (NCT02150967) in patients harboring 

 fusions presented at the 2021 Gastrointestinal Cancers Symposium. Approximately 160 patients are to be enrolled in 3 cohorts, with results from cohort 1 (n = 108) presented at the conference. ORR was observed in 23.1% (95% CI, 15.6-32.2). The ORR was higher in the second-line setting compared with third or later lines, 34% versus 13.8%, respectively. The median PFS was 7.3 months (95% CI, 5.6-7.6), and DOR was approximately 5 months (range 0.9-19.1).

Commenting on the studies with pemigatinib and infigratinib, Shroff said, “More [patients in] the infigratinib patient population have progressed on multiple lines of chemotherapy [compared with] pemigatinib. [Approximately] 60%…received pemigatinib as second-line therapy, so a little earlier than what we saw in the infigratinib data.”

Shroff added, “Interestingly, it seems the earlier use of FGFR inhibitors, in the second line for instance, produces a slightly higher response rate, suggesting that there’s utility in moving this targeted therapy into the earlier [lines of treatment].”

The third agent of interest is futibatinib, a third-generation, irreversible FGFR inhibitor. In the phase 2 FOENIX-CCA2 trial (NCT02052778), futibatinib was evaluated in 103 previously treated patients harboring 

 fusion. Data were included for 67 patients with an observed ORR of 37.3%, DCR of 82.1%, and median DOR of 8.3 months.

Adverse Effects One of the challenges of FGFR inhibitors is the associated toxicities. Adverse effects of various FGFR inhibitors are very similar due to the class effect of FGFR inhibition.

Bekaii-Saab noted, “The [adverse event] that’s very prominent or common is hyperphosphatemia, which does occur in approximately half of patients, although [there were no severe grade toxicities associated with it]. [Hyperphosphatemia] can be managed with a low phosphate diet. Occasionally we use phosphate binders and rarely we require dose reductions or interruptions.”

Shroff noted, “I think what we’ve learned is that [although] we were aggressive in managing [hyperphosphatemia], clinically it did not produce a lot of major issues.”

Other common associated adverse effects include dermatologic toxicities, diarrhea, decreased appetite, fatigue, and liver dysfunction.

“Because patients end up staying on [FGFR inhibitors] for some time, the more cumulative toxicities…are more relevant,” Shroff stated. “These include nail bed changes that can be quite disabling and painful to our patients, associated skin changes, dry mucous membrane, and stomatitis. There [are some alopecia and ocular adverse effects].…What we’ve learned over time is that [earlier treatment] and using a multidisciplinary team…[are] going to be important.”

Despite the possible adverse effects, BekaiiSaab noted, “[FGFR inhibitors] are quite safe and [toxicities are] relatively manageable for most patients, if not the overwhelming majority of patients.”

There are also several studies evaluating the use of FGFR inhibitors in the first-line treatment of patients with CCA (TABLE8-11). “These frontline studies are very important. I think it is a logical question to see if FGFR inhibitors will be able to replace gemcitabine-cisplatin [chemotherapy],” Shroff noted.

Pemigatinib is being investigated in the first-line treatment of CCA compared with standard of care chemotherapy in the phase 3, randomized, open-label FIGHT-302 study (NCT03656536). Crossover to pemigatinib is permitted upon disease progression from the chemotherapy group.

“We do think this is probably an even better role for patients with FGFR2 fusion to be exposed to these agents sooner rather than later, but that is what the study [is trying to prove],” noted Bekaii-Saab, who is the study’s principal investigator.

Infigratinib is being evaluated in the firstline setting for advanced CCA compared with chemotherapy in the phase 3 PROOF trial (NCT03773302) with planned enrollment of 384 patients with 

 Additionally, futibatinib will be evaluated in the first-line setting against standard chemotherapy for 216 patients with advanced CCA with 

 fusions in the phase 3, randomized, multicenter, open-label FOENIX-CCA3 trial (NCT04093362).

“Here’s the good news: a lot of these studies are looking at first-line [use of FGFR inhibitors],” Bekaii-Saab said. “As we keep uncovering more targets, I think we’re going to fill the landscape of cholangiocarcinoma with primarily agents that are targeted specifically for the cancer and move away from chemotherapy, at least in the first-line treatment.”

However, another challenge associated with the use of FGFR inhibitors is acquired resistance, which may develop by mutation activation or if the signaling pathway is bypassed.1 Point mutations in 

 may lead to clinical resistance of FGFR inhibitors in CCA.

 fusions are early oncogenic drivers, so [they] persist through the course of the patient’s treatment journey. Once [patients] are treated with an FGFR inhibitor, inevitably, they do develop [disease] progression and the presumption is that resistance has developed. There’s some really elegant work that has been done utilizing [circulating tumor DNA] to better understand the mechanism of resistance. What we’ve learned is that resistance is really polyclonal and often involves mutations that change the binding pocket that affects the ability of the FGFR inhibitor to bind, and some of these are what we call gatekeeper mutations,” Shroff said.

There may be differences in mutational resistance due to differing binding specificities of FGFR inhibitors, and there is evidence to suggest polyclonal resistance with multiple acquired 

 mutations in patients treated with infigratinib or pemigatinib in CCA.

 Due to the covalent bond of futibatinib to 

, there may be clinical benefit in CCA with acquired resistance to FGFR inhibitors. Additionally, strategically sequencing FGFR inhibitors may extend the duration of benefit for FGFR inhibitor use.

“There’s more to be done since we’re at the tip of the iceberg of trying to understand mechanisms of resistance with these agents,” Bekaii-Saab said. Given the challenges with FGFR inhibitor use, the future of CCA treatment is still extremely promising.

“I would imagine in the next 5 to 10 years, we’re going to continue with this positive upward trajectory and have more drugs available,” Shroff said. “I firmly believe we will move the needle forward in terms of median overall survival for this disease in the advanced setting. I think we will figure out how to integrate some of these novel targeted therapies and [potentially] immunotherapy into more localized disease and perioperative approaches…. At the end of the day, surgery is our curative treatment, and anything we can do to build on outcomes for patients [who] can undergo surgery is obviously very important.”

1. Wang J, Xing X, Li Q, et al. Targeting the FGFR signaling pathway in cholangiocarcinoma: promise or delusion? 

 2020;12:1758835920940948. doi:10.1177/1758835920940948 

2. Silverman IM, Hollebecque A, Friboulet L, et al. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib.

. 2021;11(2):326-339. doi:10.1158/2159-8290.CD-20-0766 

3. Abou-Alfa GK, Bibeau K, Schultz N, et al. Effect of FGFR2 alterations on survival in patients receiving systemic chemotherapy for intrahepatic cholangiocarcinoma. 

l. 2021;39(suppl 3):303. doi:10.1200/ JCO.2021.39.3_suppl.303 

4. FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. FDA. Updated April 20, 2020. Accessed March 5, 2021. https://bit.ly/2QomFdh 

5. Abou-Alfa GK, Sahai V, Hollebecque A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study. 

. 2020;21(5):671-684. doi:10.1016/S1470-2045(20)30109-1 

6. Javle MM, Roychowdhury S, Kelley RK, et al. Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. 

. 2021;39(suppl 3):265. doi:10.1200/JCO.2021.39.3_suppl.265

7. Goyal L, Meric-Bernstam F, Hollebecque A, et al. FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements. 

. 2020;38(suppl 15):108. doi:10.1200/ JCO.2020.38.15_suppl.108 

8. Goyal L, Shi L, Liu LY, et al. TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma. 

. 2019;9(8):1064-1079. doi:10.1158/2159-8290.CD-19-0182 

9. Bekaii-Saab TS, Valle JW, Cutsem EV, et al. FIGHT-302: phase III study of first-line (1L) pemigatinib (PEM) versus gemcitabine (GEM) plus cisplatin (CIS) for cholangiocarcinoma (CCA) with FGFR2 fusions or rearrangements. 

. 2020;38(suppl 4):TPS592. doi:10.1200/JCO.2020.38.4_suppl.TPS592 

10. Javle MM, 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;37(suppl 15):TPS4155. doi:10.1200/JCO.2019.37.15_suppl.TPS4155 

11. Borad MJ, Bridgewater JA, Morizane C, et al. A phase III study of futibatinib (TAS-120) versus gemcitabine-cisplatin (gem-cis) chemotherapy as first-line (1L) treatment for patients (pts) with advanced (adv) cholangiocarcinomva (CCA) harboring fibroblast growth factor receptor 2 (FGFR2) gene rearrangements (FOENIX-CCA3). 

. 2020;38:(suppl 4):TPS600. doi:10.1200/JCO.2020.38.4_suppl.TPS600

Articles

Although chemotherapy is the mainstay of systemic treatment for advanced cholangiocarcinoma, there are limited treatment options when the disease progresses

FGFR Inhibitors Make Inroads in Cholangiocarcinoma

Over the past several years, the oncology community has witnessed a significant improvement in identifying genetic mutations associated with increased risk of breast malignancies.

 As the understanding of genetic risk factors in breast cancer continues to grow, professional organizations have sought to provide specific recommendations for genetic testing that would prevent overtesting yet still diagnose as many mutations as possible in patients.

“In general, the gold standard [for guidelines] is clinical utility,” said Susan M. Domchek, MD, the Basser Professor in Oncology at Penn Medicine in Philadelphia, executive director of the Basser Center for 

, and director of MacDonald Women’s Cancer Risk Evaluation Center. “We’re all looking at the same data, and it just comes down to perspective for how you interpret those data.”

Currently, controversy surrounds guideline recommendations for eligibility in genetic testing. The US Preventive Services Task Force and the National Comprehensive Cancer Network (NCCN) guidelines recommend genetic testing for patients with breast cancer and a family history associated with germline 

1/2 mutations or who have a personal history with an increased risk of 

Utilizing testing criteria recommended by the NCCN may not identify a small number of individuals who have no family history but carry pathogenic variants of high-risk breast cancer genes.

“The guidelines from the NCCN focus on the likelihood of finding genes where we have specific information [on] how to use that and how helpful it is to patients, for instance, [with] BRCA and other [high-penetrance] gene mutations,” said Domchek.

Conversely, the American Society of Breast Surgeons (ASBrS) recommends genetic testing for all patients with breast cancer.

 However, the paradigm shift from genetic testing in individuals with a family history to the testing of all patients with breast cancer, as recommended by ASBrS, may lead to unnecessary testing and the potential for harm.

 The optimal model for genetic testing in patients with breast cancer has not yet been identified, though some strategies have been proposed.

According to results of a recently published single-center, prospective study, population-based genetic testing in patients with breast cancer younger than 65 years may optimize the identification of germline pathogenic variants.

 The sensitivity and specificity of NCCN and ASBrS criteria for germline pathogenic variants were assessed. The primary analysis evaluated 9 established, actionable breast cancer predisposition genes (

). In the entire population evaluated (N=3907), 6.2% had germline pathogenic variants, with 

 are challenging because they’re strongly modified by family history…so we view it as a risk factor,” Domchek said.

Approximately 48% of patients met NCCN guidelines’ criteria for genetic testing, whereas 52% of patients did not. Individuals who met NCCN criteria were more likely to have a pathogenic variant in 1 of the 9 genes, 9.0% versus 3.5%, compared with individuals who did not meet NCCN criteria (

<.001). The primary analysis revealed a sensitivity of 70.1% and a specificity of 53%. When the investigators modified the NCCN criteria to include patients who were 65 years old at the time of receiving a diagnosis and family history, the sensitivity increased to over 90% for pathogenic variants in 9 predisposition genes.

 Currently, the clinical utility in genetic testing in women over 65 years is unknown because the probability of detecting a germline pathogenic variant decreases with age.

To improve upon a previous study by Yadav et al, Desai et al proposed to test individuals with breast cancer under 60 years.4 The sensitivity for detecting pathogenic variants decreased slightly when testing patients under 60 years compared with patients who were 65 years or younger, 98.1% versus 95.3% for 

1/2, respectively. The sensitivity for detection of pathogenic variants in 6 high-risk genes also decreased with age 60 years and under compared to 65 years and under, 94.8% versus 91%, respectively. For patients who received a breast cancer diagnosis who were over 60 years, the investigators concluded that using the NCCN family-based criteria would be appropriate. However, the investigators noted there might be an increased detection of variance of unknown significance (VUS) with this approach.

In addition to the controversy of patient selection for genetic testing, a lack of consensus exists regarding the number of genes that the testing panel should include. The introduction of next-generation sequencing has allowed genetic testing to become more accessible with a lower financial burden.6 There are over 170 breast cancer susceptibility variants identified based on the largest genome-wide association study.

“Costs are coming down, but when people at low risk get genetic testing, we’re more likely to find things [such as] VUS, which are changes in the genetic code that we don’t understand, than we are to find something important. The risk-benefit ratio changes depending on [what] the risk is to begin with,” said Domchek.

A study using Surveillance, Epidemiology, and End Results (SEER) data evaluated 187,535 patients with breast cancer.

 However, only 25.2% of those patients had genetic testing analysis. This genetic testing demonstrated a prevalence of 

1/2 pathogenic variants in 5.2% of individuals, whereas other genetic variants (

) were associated with an increased risk of breast cancer in 4.9% of individuals.

“We don’t do a great job of testing individuals who currently meet testing criteria, and we have a real problem with disparity. We want to make sure that people at the highest risk are being tested. That’s a clear priority,” stated Domchek.

Another study that evaluated the prevalence of germline pathogenic variants used a US-based consortium, Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS).

 The analysis included 12 studies that were part of the population-based CARRIERS analysis with 32,247 case patients and 32,544 controls. There were 12 established breast cancer predisposition genes assessed (

). The prevalence of germline pathogenic variants in the population-based analysis was 5.03% (95% CI, 4.79%-5.27%) in case patients and 1.33% (95% CI, 1.50%-1.78%) in controls (FIGURE).

The highest rates of prevalence of pathogenic variants were seen with 

Regarding the study, Domchek said, “If you look at 12 genes that are putatively associated with breast cancer, 5% of patients have mutations in those genes, but several of those [genes] are not clearly associated with risk.”

Results also determined pathogenic variants in BRCA1 (odds ratio [OR], 7.62; 95% CI,5.33-11.27) and 

 (OR, 5.23; 95% CI, 4.09-6.77) were associated with high breast cancer risk. Moderate breast cancer risk was observed in pathogenic variants in 

 (OR, 3.83; 95% CI, 2.68-5.63; and OR, 2.47; 95% CI, 2.02-3.05), respectively.

Furthermore, different pathogenic variants were associated with specific breast cancer subtypes. Pathogenic variants in 

 placed the individual at moderate risk for estrogen receptor (ER)– negative breast cancer and triple-negative breast cancer (TNBC). Conversely, pathogenic variants in 

 were associated with ER-positive breast cancer. Additionally, there was a higher prevalence of pathogenic variants in 

 observed with TNBC compared with ER-positive breast cancer, 8.13% versus 1.84%, respectively.

Another large study analyzed data from 44 studies in the Breast Cancer Association Consortium with 60,466 patients and 53,461 controls.

 For the purpose of population-based analysis, 48,826 patients and 50,703 controls were included from the total number of individuals in the study. Results showed pathogenic variants in 5 genes were associated with an increased risk of breast cancer (

 <.0001). Additional pathogenic variants associated with high-risk breast cancer were found in 

<.05). There were also associations with pathogenic variants and different subtypes of breast cancer. As in the CARRIERS study, 

 was associated with ER-positive compared with ER-negative breast cancer (OR, 2.67; 95% CI, 2.30-3.11; vs OR, 1.64; 95% CI, 1.25-2.16). Pathogenic variants in 

 were more frequently found in ER-positive than in ER-negative breast cancer (OR, 2.33; 95% CI, 1.87-2.91; vs OR, 1.01; 95% CI, 0.64-1.59). Additionally, there were more pathogenic variants (

) associated with ER-negative compared with ER-positive breast cancer (

The appropriate identification of patients and important pathogenic variants in genetic testing may lead to optimization of care in the age of precision medicine. The results from genetic testing may have implications for patients ranging from surgical, radiation, and targeted therapeutic intervention, as well as prevention strategies for patient family members.6 Patients with 

 mutations with metastatic breast cancer may benefit from targeted therapy with PARP inhibitors.

“In the early-stage [breast cancer] setting, we’re testing 

 to talk about removal of the ovaries and the consideration for removal of the [contralateral] breast. The clearly actionable 

A population-based cohort study evaluated pathogenic variants and clinical treatment pathways in patients with breast cancer using SEER registries in 20,568 individuals.11 Patients were nonexclusively stratified into 3 separate treatment subgroups including surgery, radiation, and chemotherapy. The results demonstrated an increased prevalence of bilateral mastectomy (n=15,126) and chemotherapy treatment (n= 8509) for individuals with pathogenic variants in 

 and other genetic pathogenic variants were more likely to undergo bilateral mastectomy compared with those with VUS (OR, 5.52; 95% CI, 4.73-6.44; and OR, 2.41; 95% CI, 1.92-3.03; vs OR, 0.99; 95% CI, 0.89-1.1, respectively). Additionally, individuals with 

 and other genetic pathogenic variants were more likely to receive chemotherapy treatment compared with those with VUS (OR, 1.76; 95% CI, 1.31-2.34; and OR, 1.27; 95% CI, 0.87-1.86; vs OR, 0.95; 95% CI, 0.81-1.11, respectively). There is currently no consensus on patient selection or gene selection.

“Our goal is to make sure that every candidate who is a good candidate for genetic testing gets tested regardless of their race, ethnicity, or socioeconomic status. Family history should be taken, and [patients] should know about the availability of testing and be counseled on their level of risk,” said Domchek. “This is the intersection among regulations, insurance coverage, and prior probability. I do think that genetic testing is only going to become more widespread, and our job is to make sure that patients understand what tests are being sent and the potential implications of the results.”

1. NCCN. Clinical Practice Guidelines in Oncology. Genetic/familial highrisk assessment: breast, ovarian, and pancreatic, version 2.2021. Accessed February 8, 2021. https://bit.ly/3uc4qqY 

2. BRCA-related cancer: risk assessment, genetic counseling, and genetic testing. US Preventive Services Task Force. August 20, 2019. Accessed February 8, 2020. https://bit.ly/37o7EOo 

3. Manahan ER, Kuerer HM, Sebastian M, et al. Consensus guidelines on genetic testing for hereditary breast cancer from the American Society of Breast Surgeons. 

. 2019;26(10):3025-3031. doi:10.1245/ s10434-019-07549-8

Desai NV, Yadav S, Batalini F, Couch FJ, Tung NM. Germline genetic testing in breast cancer: rationale for the testing of all women diagnosed by the age of 60 years and for risk-based testing of those older than 60 years. 

. Published online November 4, 2020. doi:10.1002/cncr.33305

Yadav S, Hu C, Hart SN, et al. Evaluation of germline genetic testing criteria in a hospital-based series of women with breast cancer. 

. 2020;38(13):1409-1418. doi:10.1200/JCO.19.02190

Angeli D, Salvi S, Tedaldi G. Genetic predisposition to breast and ovarian cancers: how many and which genes to test? 

. 2020;21(3):1128. doi:10.3390/ijms21031128

Zhang H, Ahearn TU, Lecarpentier J, et al. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses. 

. 2020;52(6):572-581. doi:10.1038/ s41588-020-0609-2

Kurian AW, Morrow M, Katz S. Trends in genetic testing and results for women diagnosed with breast cancer or ovarian cancer, 2013-2017. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-12, 2020; virtual. Abstract PD10-01.

Hu C, Hart SN, Gnanaolivu R, et al. A population-based study of genes previously implicated in breast cancer. 

. 2021;384(5):440- 451. doi:10.1056/NEJMoa2005936

Breast Cancer Association Consortium, Dorling L, Carvalho S, et al. Breast cancer risk genes - association analysis in more than 113,000 women. 

. 2021;384(5):428-439. doi:10.1056/NEJMoa1913948

Kurian AW, Ward KC, Abrahamse P, et al. Association of germline genetic testing results with locoregional and systemic therapy in patients with breast cancer. 

. 2020;6(4):e196400. doi:10.1001/jamaoncol.2019.6400

As the understanding of genetic risk factors in breast cancer continues to grow, professional organizations have sought to provide specific recommendations for genetic testing that would prevent overtesting yet still diagnose as many mutations as possible in patients.

Next-Generation Sequencing Informs Genetic Testing in Breast Cancer

In recent months, PARP inhibitors have propelled the field of metastatic castration-resistant prostate cancer (mCRPC) forward as the next class of therapeutics to advance outcomes. Approvals for 2 PARP agents, along with data from major medical conferences regarding the use of immunotherapeutics and other anticancer agents, show promise for the treatment of patients with advanced disease.

“We always knew that it was a matter of time for PARP inhibitors to get approved for patients with metastatic prostate cancer,” said 

). He is a professor in the Division of Oncology, Department of Medicine, at the University of Utah School of Medicine, and director of the Genitourinary Oncology Program at the Huntsman Cancer Institute in Salt Lake City.

The PARP inhibitor olaparib (Lynparza) gained FDA approval for treatment of mCRPC in May 2020, and was the first approval for this class of agent in prostate cancer with supporting efficacy data based on a randomized phase 3 clinical trial. The PROfound trial (NCT02987543) demonstrated improved radiographic progression-free survival (rPFS) with olaparib versus either enzalutamide (Xtandi) or abiraterone acetate (Zytiga) in patients whose mCRPC had deleterious or suspected deleterious germline or somatic mutations in homologous recombination repair (HRR) genes (7.4 months vs 3.6 months; HR, 0.34; 

“These were remarkable findings...olaparib was clearly superior by almost 4 months,” Agarwal said.

PARP Inhibitors in Advanced Prostate Cancer

PARP enzymes play a critical role in repairing single-strand DNA breaks. With the use of PARP inhibitors, these lesions remain unrepaired and often progress to double-strand breaks (DSBs), which are preferentially resolved by HRR. However, germline or somatic homologous recombination deficiency (HRD), which is present in up to 25% of patients with mCRPC, obliges tumor cells to repair DSBs via an error-prone alternative pathway, nonhomologous end joining (NHEJ). The genetic aberrations introduced by NHEJ often irreparably damage key cellular pathways, dooming cancer cells to apoptosis—hence the keen interest in treating tumors with HRD using PARP inhibitors.

 With limited treatment options for mCRPC, the development of PARP inhibitors has provided an important lifeline in this population, especially in the HRD setting (

The pivotal PROfound study was a prospective, randomized, multicenter, open-label, phase 3 clinical trial that randomized patients 2:1 to receive either olaparib or androgen receptor–targeted therapy (ART) consisting of enzalutamide or abiraterone. Patients with mutations in HRR genes 

made up cohort A (olaparib group, n = 162; ART group, n = 83). Patients with a mutation in any of 12 other HRR genes were treated in cohort B (olaparib; n = 94; ART, n = 48).

“The secondary analysis looking at additional genes [in cohort B] was exploratory; however, the exploratory analysis was only possible and statistically permitted if the primary analysis for 

, professor of oncology and urology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, said in an interview with 

. After the primary end point of rPFS in cohort A was met, a review of both cohorts combined demonstrated improvement in rPFS, at 5.8 months for olaparib versus 3.5 months with ART (HR, 0.49; 95% CI, 0.38-0.63; 

Additionally, an interim analysis showed that median overall survival (OS) in cohort A was 18.5 months with olaparib versus 15.1 months with ART (HR, 0.64; 95% CI, 0.43-0.97; 

= .02). This difference did not achieve statistical significance, however, due to the preset cutoff of 

“Patients who were randomized to the enzalutamide or abiraterone arm were allowed to cross over to the olaparib arm at the time of disease progression, and a large number of patients [82%] actually crossed over. Despite the crossover, the median OS [benefit] remained significant, at 3 months higher compared with abiraterone or enzalutamide,” Agarwal said. The interim median OS analysis of both cohorts significantly favored olaparib, at 17.5 months versus 14.3 months with ART (HR, 0.67; 95% CI, 0.49-0.93; 

Other secondary end points, including objective response rate (ORR) and median time to pain progression in cohort A, also significantly favored olaparib. Common adverse events (AEs) that occurred with olaparib included anemia, nausea, and fatigue or asthenia. Additionally, grade 3 or higher AEs occurred more frequently with olaparib compared with ART.

“I think the PROfound trial is the first large phase 3 randomized trial that showed a PARP inhibitor is superior to these standard-of-care [therapies] for patients who have disease progression on abiraterone or enzalutamide and are harboring mutations in DNA repair genes. It’s a very exciting development that’s happened in the last few months,” Agarwal said.

Further support for olaparib use in mCRPC was demonstrated in the phase 2 TAPUR trial (NCT02693535). Patients in this trial had exhausted all standard options, harbored germline or somatic 

mutations, had an ECOG performance score of 2 or less, had measurable disease, and had adequate organ function. The disease control rate was 68% (90% CI, 53%-77%) in the 25 patients evaluated. The interim median OS was 75.3 weeks (95% CI, 49.1-88.9). The results of this study demonstrated the utility of olaparib as a therapy option in patients with heavily pretreated mCRPC harboring germline or somatic 

Another PARP inhibitor that recently received accelerated approval for mCRPC is rucaparib (Rubraca).

 The TRITON2 trial (NCT02952534) showed encouraging antitumor activity of rucaparib in 57 patients with 

mutations, with an ORR of 43.9% (95% CI, 30.7%-57.6%).

There were 2 distinct differences between the patient groups approved for this PARP inhibitor and for olaparib, Agarwal indicated. The first was treatment history; consistent with the PROfound trial’s eligibility requirements, olaparib approval specified that patients need only have progressed on ART. “Rucaparib was approved based on the TRITON2 trial, in which patients had received both abiraterone or enzalutamide and docetaxel chemotherapy,” Agarwal noted.

“The number of eligible genes also differs. Rucaparib is only approved for 

[mutations],” Agarwal added, which contrasts with olaparib’s approval for mCRPC associated with mutations in multiple HRR genes.

Antonarakis also noted some differences in the AE profiles of the 2 drugs: “The adverse effects that grabbed my attention [that] were present with olaparib and perhaps not with rucaparib were…a slightly higher risk of venous thromboembolic events…and a rare, but serious, [risk of] pneumonitis.”

Additional PARP Inhibitors on the Horizon

Other PARP inhibitors that show potential for FDA approval in mCRPC include niraparib (Zejula) and talazoparib (Talzenna). Niraparib is being explored in the setting of 

mutations after disease progression on ART and taxane chemotherapy. It was granted breakthrough therapy designation by the FDA based on the phase 2, multicenter, open-label GALAHAD trial (NCT02854436).

 Based on data presented at the European Society for Medical Oncology 2019 Congress, the agent demonstrated a 41% ORR in patients with mCRPC who have 

Talazoparib has also demonstrated benefit in patients with mCRPC driven by alterations in 

or other DNA damage repair genes after treatment with at least 1 taxane chemotherapy regimen and ART. An interim analysis of the TALAPRO-1 trial (NCT03148795) showed an ORR of 25.6% (95% CI, 13.5%-41.2%) in the overall cohort. The ORR was higher, at 50.0% (95% CI, 27.2%-72.8%), in the subset of patients with 

Commenting on the future of PARP inhibitors, Agarwal predicted that “there will be a time soon [when] we will be testing these PARP inhibitors in the up-front setting in patients with newly diagnosed prostate cancer who are harboring mutations in DNA repair genes.”

With the recent approvals of PARP inhibitors, the National Comprehensive Cancer Network has updated its guidelines to recommend tumor testing for HRR mutations. Additionally, both olaparib and rucaparib have been added to the list of systemic therapy options for patients with HRR-mutated mCRPC to reflect the current standard of care.

Antonarakis noted that in addition to PARP inhibition, “one of the most exciting developments [in prostate cancer treatment is the use of] radioligand treatment that targets prostate-specific membrane antigen [PSMA]–expressing prostate cancer. PSMA is almost ubiquitous in prostate cancer in castration-resistant disease and is present in more than 80% to 90% of castration-resistant metastasis. It’s a very reasonable target.”

The phase 2 TheraP trial (NCT03392428) randomized patients with mCRPC who had progressed after docetaxel to treatment with either lutetium 177–labeled PSMA-617 (177Lu-PSMA-617; LuPSMA) or cabazitaxel (Jevtana; a taxane). Antonarakis explained that Lu-PSMA “is a radioligand whereby a radioactive molecule, lutetium, gives off a type of radiation called b waves [and] binds to prostate cancer cells that are expressing PSMA. The lutetium is used to irradiate the cells that it binds.”

Patients were randomized to either Lu-PSMA (n = 98) every 6 weeks for up to 6 cycles or cabazitaxel (n = 85) every 3 weeks for up to 10 cycles. The percentage of patients meeting the primary end point of prostate-specific antigen (PSA) response rate (PSA reduction ≥50% from baseline) was almost doubled in the Lu-PSMA group compared with the cabazitaxel arm, at 66% versus 37%, respectively (

< .0001). A sensitivity analysis also favored the experimental arm and demonstrated a 23% difference in PSA response rate (

= .0016). Preliminary results demonstrated improved PSA PFS (defined as time from randomization to PSA progression) at a median follow-up of 13.3 months (HR, 0.69; 95% CI, 0.50-0.95; 

Additionally, grade 3/4 AEs occurred less frequently in the Lu-PSMA group (35%) compared with the cabazitaxel group (54%). Diarrhea, dysgeusia, and neuropathy of any grade occurred more frequently with cabazitaxel, whereas thrombocytopenia, dry mouth, and dry eye occurred more frequently with Lu-PSMA. Results of this study indicate that Lu-PSMA represents a potential novel class of effective therapy for mCRPC after progression on taxane chemotherapy.

“The theoretical advantage of Lu-PSMA…is that it will target bone and nonbone lesions—for example, soft tissue metastases,” Antonarakis said. “The phase 3 study with Lu-PSMA [VISION trial; NCT03511664] is awaiting results. Many of us in the field anticipate that Lu-PSMA will be FDA approved by the middle of 2021.”

Another notable study is the CARD trial (NCT02485691), which evaluated the use of cabazitaxel (n = 129) versus ART (n = 126; abiraterone or enzalutamide) after previous docetaxel and within 12 months of progression on ART. This was a multicenter, randomized, open-label trial with rPFS as the primary end point. The median follow-up was 9.2 months. Cabazitaxel improved median rPFS by more than 4 months compared with ART, at 8.0 months versus 3.7 months (HR, 0.54; 95% CI, 0.40-0.73; 

< .0001). Additionally, cabazitaxel improved median OS compared with ART, at 13.6 months versus 11.0 months (HR, 0.64; 95% CI, 0.46-0.89; 

Furthermore, analyses evaluating OS from various starting points—including diagnosis of metastatic disease, diagnosis of mCRPC, and initiation of first and second life-extending therapies—all favored cabazitaxel over ART. The survival benefit of cabazitaxel compared with ART was supported by a stratified multivariate analysis. Results of the CARD study support cabazitaxel over ART as the standard of care for patients previously treated with docetaxel and ART.

“What the CARD trial has taught us is that we should alternate ART with taxane chemotherapy,” Antonarakis said.

The pivotal CARD trial inspired the creation of other studies to evaluate different end points and patient populations. One of these studies was PROREPAIR-B (NCT03075735), a prospective trial evaluating the effects of germline mutations in HRR genes on the benefit of first, second, and subsequent lines of therapy. Of the 419 patients in this trial, 95 met the same inclusion criteria as those for the CARD study.

In the overall population, cabazitaxel (n = 60) demonstrated improved rPFS compared with ART (n = 35; abiraterone/enzalutamide), at 6.0 months versus 3.7 months, respectively (

= .03). No difference in OS was detected, perhaps due in part to the 60% rate of crossover from ART to cabazitaxel. However, subgroup analyses revealed that patients with germline HRR mutations had a significantly worse prognosis, with poor hazard ratios for OS (HR, 1.9) and rPFS (HR, 2.4), as well as no improvement in OS (4.5 months vs 3.7 months; 

= .8) or rPFS (2.5 months vs 3.8 months; 

= .8) with cabazitaxel compared with ART. The PROREPAIR-B findings further support the results of the CARD trial for unselected patients, favoring the use of cabazitaxel over ART.

However, the poor outcomes with both regimens in patients with germline HRR–mutant mCRPC support the need for novel treatments in this setting.13 “There is accumulating evidence, although it’s not conclusive yet, that perhaps patients with HRR mutations—especially 

] germline mutation—may actually be a bit more taxane resistant and more hormone therapy sensitive, which might sound like a bit of a paradox,” Antonarakis said. “The [data] are immature but provocative…and should be further studied.”

In a preplanned analysis of the CARD trial, patient-reported outcomes were evaluated using a questionnaire, the EuroQol Group’s 5-dimension, 5-level (EQ-5D-5L) utility index score and visual analogue scale (VAS). The investigators evaluated the scores at baseline, on day 1 of each cycle, and at the end of treatment. At baseline, patients randomized to the cabazitaxel versus ART groups had similar EQ-5D-5L utility index scores (0.7 in both groups) and VAS (65.8 with cabazitaxel vs 66.3 for ART). Pain response (a reduction in pain from baseline) was reported in a significantly greater proportion of the cabazitaxel group (45.9%) compared with the ART group (19.3%; 

< .0001). Cabazitaxel also delayed the time to pain progression compared with ART (HR, 0.55; 95% CI, 0.32-0.97; 

= .03). Additionally, the safety profile of cabazitaxel was manageable, with fewer grade 3 or higher cardiac disorders compared with ART (0.8% vs 4.8%).

As another novel approach for treating mCRPC, immunotherapeutics are making their way into the treatment landscape. Agarwal remarked that because “cabozantinib [Cabometyx] and atezolizumab [Tecentriq] have synergistic action…they were found to suppress the immune-suppressive cells and upregulate immunostimulatory cells.”

This was the rationale for exploring the small-molecule multityrosine kinase inhibitor/PD-L1 inhibitor combination of cabozantinib and atezolizumab in the phase 1b COSMIC-021 (NCT03170960) trial, with multiple cohorts of patients with 1 of 12 types of advanced solid tumors, including mCRPC. Patients enrolled in cohort 6 had mCRPC with radiographic progression in soft tissue after ART, measurable disease, and an ECOG performance status of 0 or 1. The primary end point of ORR was 32% (80% CI, 23%-42%) for the first 44 patients enrolled, including 3 patients with complete responses and 11 who achieved partial responses. Furthermore, 21 patients (48%) achieved stable disease, for a disease control rate of 80%.

PARP inhibitors have propelled the field of metastatic castration-resistant prostate cancer forward as the next class of therapeutics to advance outcomes.

Thao K . Huynh, PharmD , BCOP | Authors

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