In an analysis of the phase III STORM trial, 2 biomarkers were found that were indicative of patients&rsquo; responses; however, no predictive biomarkers were found to identify patients with a greater risk for recurrence following sorafenib.

The STORM trial demonstrated no significant difference in recurrence-free survival (RFS), time to recurrence, and overall survival for patients being treated with adjuvant sorafenib versus placebo. However, due to the adjuvant trial design, tissue samples were evaluated for biomarker analysis aimed at determining the molecular prognostic factors and predictors of recurrence with sorafenib.

Overall, no biomarkers related to angiogenesis, proliferation, previously proposed gene signatures, or mutations were independently associated with recurrence or prevention for treatment with sorafenib. Recurrence often occurs after resection in 70% of patients at 5 years, according to Robert Montal, MD, a visiting researcher at Mount Sinai Health System.

&ldquo;The idea of the companion biomarker clinical trial was to infer molecular alterations that could discriminate [between] the subpopulation of patients who could benefit from sorafenib in the adjuvant setting,&rdquo; said Montal in an interview with

The STORM trial collected tumor samples from 188 patients with resected HCC, 83 of which were treated with sorafenib, and 105 patients with placebo. Prognostic and predictive biomarkers were analyzed by gene expression, targeted exome sequencing of 18 mutational drivers, assessment of activation of MAPK signaling, and angiogenesis.

Positive hepatocyte pERK staining (hazard ratio [HR], 2.41; 95% CI, 1.21-4.8; P = .012) and microvascular invasion were independent prognostic factors in regard to predictive variables for RFS. In the STORM trial, RFS events (recurrences) occurred in 70 cases.

There was an association found between hepatocyte pERK-positive and proliferation gene signatures (P <.001), poor differentiation (P = .01), and Ki-67 positivity (P <.05).

The STORM trial did not identify candidate biomarkers predicting recurrence prevention with sorafenib. Biomarkers related to angiogenesis, proliferation, previously proposed gene signatures, or mutations were not independently associated with recurrence or prevention with sorafenib.

However, the investigators generated a multigene signature that did correlate with improved RFS with sorafenib versus placebo, but this would require external validation.

&ldquo;None of the prespecified biomarkers obtained the statistically significant results in terms of the prediction of benefit to sorafenib,&rdquo; Montal explained. &ldquo;We designed a gene signature composed of 146 genes that are able to identify those patients in our cohort who benefit from sorafenib, but certainly, these gene signatures should be externally evaluated for assessing its clinical validity.&rdquo;

Questions remain in determining how to incorporate biomarkers into clinical practice for HCC, especially when using them to identify patients who would best respond to current and emerging therapies.

&ldquo;In HCC, and similar to other solid tumors, these predictive biomarkers have not been incorporated yet in the clinical practice. In fact, most of the phase III trials assessing new drugs in HCC have failed targeting all-comers. The idea would be to start the development of new drugs in HCC together with the predictive biomarkers from the further stems of the clinical research,&rdquo; said Montal.

Another area of increasing interest regarding biomarkers for HCC is the development and optimization of liquid biopsies to help determine the biology of tumors. Additionally, the survival benefit shown with systemic therapies in phase III trials, with sorafenib, regorafenib (Stivarga), and lenvatinib (Lenvima), is continuing to be investigated. Immune checkpoint inhibitors are also being studied in HCC as they have dramatically changed the standard of care in other solid tumors, most notably in nonsmall cell lung cancer, melanoma, and urothelial carcinoma. In liver cancer, the PD-1 inhibitor nivolumab (Opdivo) recently received an accelerated approval from the FDA for the treatment of patients with HCC following treatment with sorafenib.

Pinyol R, Montal R, Takayama T, et al. Molecular predictors of recurrence prevention with sorafenib as adjuvant therapy in hepatocellular carcinoma: biomarker study of the STORM phase III trial. J Hepatol. 2017;66(1):S12-S13. doi: 10.1016/s0168-8278(17)30287-8.

Pinyol R, Montal R, Quetglas IM, et al. Molecular predictors of recurrence prevention with sorafenib as adjuvant therapy in hepatocellular carcinoma: biomarker study of the STORM phase III trial. In: Proceedings from the 11th International Liver Cancer Association Annual Conference; September 15 to 17, 2017; Seoul, South Korea. Abstract 0-002.

Articles

Clinical Articles

Researchers are seeking prognostic biomarkers for response to treatment with adjuvant sorafenib (Nexavar) in patients with hepatocellular carcinoma, according to a presentation during the&nbsp;2017 International Liver Cancer Association Annual Conference in Seoul, South Korea.

Predictive and Prognostic Biomarkers Sought in HCC

An overall response rate of 16% (95% CI, 6%-31%) was demonstrated in patients with FGF 19 immunohistochemistry (IHC)-positive hepatocellular carcinoma (HCC) treated with BLU-554, which was higher than the response rates of 10% or less that are seen with the currently approved HCC treatments, according to a presentation during the 2017 International Liver Cancer Association Annual Meeting.

Liver cancer is the second leading cause of cancer-related deaths worldwide, and HCC is the most common form of the disease. In the United States, HCC is the fastest rising cause of cancer-related death. Over the past 2 decades, the incidence of HCC has tripled and the 5-year survival rate has remained below 12%.

&ldquo;Patients with hepatocellular carcinoma face a very poor prognosis with few therapeutic options,&rdquo; said lead investigator Richard Kim, MD, associate professor, Moffitt Cancer Center. &ldquo;The new BLU- 554 data [presented] showed that in heavily pretreated patients, BLU-554 demonstrated encouraging clinical activity, with approximately half of patients with FGF 19 IHC-positive HCC having tumor shrinkage. These data compare well to historical data for currently approved agents showing response rates of approximately 10% or less, and BLU-554 has the potential to change the treatment paradigm for patients with FGF 19 IHC-positive HCC.&rdquo;

As of the data cutoff date of August 18, 2017, 49% of patients with FGF 19 IHC-positive HCC had radiographic tumor reduction.

In an interview with Targeted Therapies in Oncology&trade;, Kim explained that BLU-554 is an irreversible kinase inhibitor that &ldquo;exquisitely&rdquo; binds to fibroblast growth factor receptor 4 (FGFR4) and does not bind to other receptors. Investigators have also identified FGF 19 as a potential biomarker that may predict response to the drug. He said the research team plans to finish the expanded cohort in the phase I study and add more patients who are kinase-na&iuml;ve in order to gather more efficacy data in that setting.

These results include an analysis of the first 77 patients enrolled in the dose-escalation and -expansion portions of the phase I clinical trial, which ranged from 140 to 900 mg of BLU-554 daily. The group included 44 patients with FGFR4-driven HCC, defined as at least 1% tumor expression of FGF19.

These patients were heavily pretreated. More than 4 in 5 patients underwent prior tyrosine kinase inhibitor (TKI) treatment, 23% received prior immunotherapy, and 91% received prior systemic therapy.

The dose-escalation portion of the trial established 600 mg of daily BLU-554 as the maximum-tolerated dose, and investigators are currently recruiting patients for the expansion portion of the trial at that dose.

The disease control rate was 68%. One patient had an unconfirmed complete response, 5 patients had partial responses (4 confirmed), and 20 patients had stable disease. Investigators found that patients who were FGF 19 IHC-negative (n = 29) did not demonstrate response to BLU-554.

&ldquo;It is clear that patients with HCC who are FGF 19 IHC-negative do not respond to BLU-554,&rdquo; Kim said. &ldquo;On the other hand, relative response is 16% in HCC patients who are FGF 19-positive, [which is very similar to that seen with] nivolumab (Opdivo) in the second-line setting.&rdquo;

He added that most patients in this study failed on TKI treatment. Future research will focus on TKI-na&iuml;ve patients with FGF19-positive tumors.

Most adverse events (AEs) were grade 1/2. The most common all-grade treatment-related AEs reported by investigators included diarrhea (71%), nausea (42%), vomiting (36%), transaminase elevation (AST 34% and ALT 32%), and fatigue (29%). Grade &ge;3 treatment-related AEs observed in 5 or more patients included anemia, diarrhea, and transaminase elevation (AST and ALT).

Fifty-eight patients discontinued treatment with BLU-554. Forty-two stopped due to disease progression, 11 due to treatment-related AEs, 2 due to the investigator&rsquo;s decision, and 3 withdrew their consent.

Kang Y-K, Macarulla T, Yau T, et al. Clinical activity of Blu-554, a potent, highly-selective FGFR4 inhibitor in advanced hepatocellular carcinoma (HCC) with FGFR4 pathway activation. Presented at: 2017 ILCA Annual Conference; September 15-17, 2017; Seoul, South Korea. Abstract O-032.

An overall response rate of 16% was demonstrated in patients with FGF 19 immunohistochemistry-positive hepatocellular carcinoma treated with BLU-554, which was higher than the response rates of 10% or less that are seen with the currently approved HCC treatments.

FGFR4 Inhibitor Demonstrates Promising Activity in HCC Subgroup

A multidisciplinary set of guidelines for the treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) has been created as a result of a new collaboration between the American Urological Association (AUA) and several other prominent urological groups.

The new guidelines provide a risk-stratified clinical framework to better diagnose, treat, and manage the disease.

The guideline statements included input from the AUA, American Society of Clinical Oncology, the Society of Urologic Oncology, the American Society for Radiation Oncology, and the Bladder Cancer Advocacy Network. This first-of-its-kind collaboration offers clinicians evidence-based recommendations of 3 levels (A, B, and C); clinical principle statements that all clinicians or urologists generally agree upon; and expert opinions that express the unanimous conclusions of the panelists.

There is a clinical need for improved management of patients with MIBC, as 79,030 new cases of bladder cancer and 16,870 deaths from the disease are predicted for 2017 in the United States.

&ldquo;Approximately 25% of newly diagnosed patients have muscle-invasive disease, and that rate hasn&rsquo;t changed over the past 25 years. In addition, the overall prognosis of patients with muscle-invasive disease has not changed in the last 30 years and is primarily based on stage,&rdquo; said Jeffrey M. Holzbeierlein, MD, a member of the panel that put together the guidelines, and director of urologic oncology at the University of Kansas Medical Center, in his presentation of the new guidelines during the 2017 American Urological Association Annual Meeting.

The first series of guidelines includes statements regarding the need for staging evaluation during physical examination of patients under anesthesia. &ldquo;The panel felt that this was an important component of identifying patients [whose tumors] might be resectable, and, of course, you would do this if you suspect MIBC at the time of [transurethral resection of bladder tumor (TURBT)]. Also, since there are a lot of comorbidities, this is a critical component to assess patients to determine what they might be candidates for in terms of treatment,&rdquo; Holzbeierlein said.

Although imaging and lab evaluation are critical components of staging patients with MIBC, the panel did not recommend any specific imaging modalities. The panel, however, did agree that cross-section imaging of the abdomen and pelvis should be done with intravenous contrast, as well as recognized that there are no data to support any single imaging modality over another. The guidelines do not recommend PET scans, as the panel said there was insufficient evidence to support their superiority over CT scans.

They did note that PET imaging should be reserved for patients with abnormal chest, abdominal, or pelvic images that require further evaluation or in cases where a lymph node biopsy is not feasible.

Although chest imaging is somewhat controversial, the new guidelines recommend a chest CT scan if the patient has a history of smoking. &ldquo;We do recognize that we are seeing increased amounts of variant histology, and when that is suspected, we recommended a review by a dedicated GU pathologist, as the definitive histology can change treatment in up to one-third of patients,&rdquo; Holzbeierlein commented.

The guidelines recommend that patients receive an explanation of all treatment options that are available, including surgery, chemotherapy, and radiotherapy. &ldquo;We recognize that not all clinicians have the ability to provide 3 different disciplines, but certainly 1 clinician can provide an explanation of the multidisciplinary approaches to treatment options that are available,&rdquo; he said.

The implications of various treatments on quality of life should also be discussed with the patient, and this is expressed as a clinical principle in the guidelines.

The treatment guidelines strongly recommend neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy based on 2 completed trials that showed improved survival in patients with MIBC using this treatment regimen.

The panel recognized that there are currently no validated predictive factors or clinical characteristics that anticipate a patient&rsquo;s response to neoadjuvant chemotherapy, but Holzbeierlein noted that there is an ongoing trial to determine these factors. He also said that the best regimen and duration for cisplatin-based chemotherapy have not yet been identified for patients with MIBC and that the decision regarding eligibility for cisplatin-based neoadjuvant chemotherapy should be based on comorbidities and performance status.

The panel did not recommend carboplatin-based chemotherapy in the guidelines. &ldquo;In fact, if the patient is not eligible for cisplatin-based neoadjuvant chemotherapy, the panel recommends moving on directly to definitive locoregional therapy, such as radical cystectomy,&rdquo; Holzbeierlein said. This conclusion is based on currently insufficient evidence for carboplatin as an effective neoadjuvant chemotherapy for patients with MIBC, as well as small, randomized studies in metastatic disease that suggest an inferior response.

Based on an expert opinion, the guidelines recommend moving from neoadjuvant chemotherapy to radical cystectomy as quickly as possible, between 4 and 8 weeks after the patient has completed and recovered from neoadjuvant chemotherapy. For patients who are eligible for cisplatin-based neoadjuvant chemotherapy but did not receive it and who have T3, T4, or node-positive disease, the guidelines recommend adjuvant cisplatin-based chemotherapy.

&ldquo;There have never been any randomized, controlled trials that have shown a significant benefit, but the meta-analyses have suggested a benefit, and therefore we recommend this option,&rdquo; Holzbeierlein commented.

The guidelines strongly recommend that clinicians offer radical cystectomy with bilateral pelvic lymphadenectomy for patients with resectable nonmetastatic MIBC. The guidelines also strongly recommend that in males, radical cystectomy include removal of the bladder, prostate, and seminal vesicles. In females, the removal of the bladder, uterus, fallopian tubes, ovaries, and anterior vaginal wall are recommended. &ldquo;Of course, clinicians should discuss the consideration of sexual function preservation and organ preservation, such as the anterior vaginal wall, based on the patient&rsquo;s specific disease characteristics,&rdquo; Holzbeierlein said.

When urinary diversion is called for, it is a clinical principle that clinicians should have a discussion with the patient regarding all options, including ileal conduit, continent cutaneous, and orthotopic neobladder urinary diversions. Holzbeierlein said that although there was discussion about ways of identifying preoperatively whether a patient was a candidate for an orthotopic neobladder, the guidelines state, as a clinical principle, that clinicians verify a negative urethral margin at the time of the surgery.

For perioperative management, the panel&rsquo;s opinion was that clinicians should optimize recovery from radical cystectomy by offering patients nutrition counseling or encouraging them to enroll in smoking cessation programs. The guidelines strongly recommend perioperative pharmacologic thromboembolic prophylaxis for patients undergoing radical cystectomy. This is because many of these patients have several risk factors associated with the development of a thrombosis.

The guidelines also strongly recommend mu-opioid antagonist therapy for bowel recovery after surgery. It was also stated that prior to leaving the hospital, patients should be educated regarding any type of urinary diversion that they have, ideally by an enterostomal therapist if the patient has an ileal conduit.&nbsp;

The guidelines recommend that clinicians perform a bilateral pelvic lymphadenectomy at the time of any surgery, with curative intent. &ldquo;The extent of lymphadenectomy remains somewhat unknown at this time,&rdquo; Holzbeierlein said. &ldquo;We recommend at least removal of the external, internal, and obturator lymph nodes, and we would recommend that at least 12 lymph nodes would be removed, as this was felt to be a good surrogate for an adequate lymphadenectomy.&rdquo;

It was stated as a clinical principle that doctors should discuss bladder preservation with all patients, and for patients with newly diagnosed, nonmetastatic MIBC who desire to retain their bladder or are unfit for radical cystectomy, clinicians should offer bladder preservation therapies.

In terms of bladder preservation strategies, &ldquo;The panel&rsquo;s preferred strategy is using a multimodal approach, which combines maximal TURBT, systemic chemotherapy, radiation therapy, and ongoing cystoscopy, to evaluate response and identify recurrences,&rdquo; Holzbeierlein said. The guidelines recommend that prior to bladder preservation therapy, all patients undergo maximal debulking TURBT and an assessment for the presence of multifocal disease, such as carcinoma in situ. However, the guidelines do not recommend TURBT and partial cystectomy for patients who are surgical candidates, nor primary radiation therapy for this patient population.

For patients with MIBC who have chosen multimodal bladder preservation therapy, the guidelines strongly recommend that clinicians offer maximal transurethral resection of the bladder tumor, chemotherapy combined with external beam radiation therapy, and planned cystoscopic reevaluation. Further, the guidelines recommend that radiation-sensitizing chemotherapy regimens include cisplatin or fluorouracil and mitomycin C. Following bladder preservation therapy, they advise that clinicians perform regular surveillance with CT scans, cystoscopy, and urine cytology.

Notably, those who are biopsy-proven complete responders to bladder-preserving protocols remain at risk for invasive and noninvasive recurrences, as well as new tumors in the upper urinary tracts, although these recurrences may be successfully managed by prompt salvage therapy, according to Holzbeierlein. For patients who have unsuccessful bladder preserving treatment, cystectomy is strongly recommended for those who qualify. If patients have nonmuscle invasive recurrences, then they can undergo TURBT with intravesical therapies.

When it comes to patient surveillance and follow-up, the guidelines state that for all patients, clinicians should obtain chest and cross-sectional imaging of the abdomen and pelvis with CT or MRI at 6- to 12-month intervals for 2 to 3 years and continue annually. &ldquo;We do recommend cross-sectional imaging and laboratory assessments every 3 to 6 months for 2 to 3 years after cystectomy or after bladder-preservation therapy and annually thereafter,&rdquo; said Holzbeierlein. If a patient has urethral remnant, those patients should be monitored. Although the data do not support a survival advantage for urethral washes,

the panel concluded that those may be considered an option.

Patient survivorship is also stressed in the guidelines. Clinicians should discuss with their patients how they are coping with their bladder cancer diagnosis and treatment. &ldquo;For patients who have undergone cystectomy, we recommend participating in a cancer support group, as well as adoption of healthy lifestyles,&rdquo; Holzbeierlein added.

&ldquo;Variant histology is something that is an evolving topic within the MIBC guidelines and may require diversion from these guidelines,&rdquo; Holzbeierlein commented. The guidelines recommend that for patients diagnosed with variant histology, clinicians consider diverging from standard evaluation and management for urothelial carcinoma.

According to Holzbeierlein, the most appropriate care and evaluation of variant histologies could be better understood as more are recognized over time. Thus, previous recommendations may not apply to a small, but significant, number of patients.

Several other key areas deserve attention to improve care and outcomes for patients with MIBC. Enhanced detection of bladder cancer cells through imaging technologies or other means is necessary to identify patients with high-risk and advanced disease. Additionally, the growth and introduction of novel immunotherapies for treating bladder cancer has already shown much promise, with phase II and III trials demonstrating significant antitumor activity. According to Holzbeierlein, there is also a need to establish the roles of specific imaging and laboratory tests and their appropriate spacing. Future studies are needed to define patient-specific approaches to detection of MIBC, therapy, and optimal strategies for surveillance after definitive treatment.

Chang SS, Bochner BH, Chou R, et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J Urol. 2017;198(3):552-559.

Siegel RL, Miller KD, Jeman A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30. doi: 10.3322/caac.21387.

Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-866. doi: 10.1056/NEJMoa022148.

Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK; International Collaboration of Trialists; Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group); European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group; et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29(16):2171-2177. doi: 10.1200/JCO.2010.32.3139.

Dreicer R, Manola J, Roth BJ, et al. Phase III trial of methotrexate, vinblastine, doxorubicin, and cisplatin versus carboplatin and paclitaxel in patients with advanced carcinoma of the urothelium. Cancer. 2004;100(8):1639-1645. doi: 10.1002/cncr.20123.

Dogliotti L, Carteni G, Siena S, et al. Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol. 2007;52(1):134-141. doi: 10.1016/j.eururo.2006.12.029.

Forrest JB, Clemens JQ, Finamore P, et al; American Urological Association. AUA best practice statement for the prevention of deep vein thrombosis in patients undergoing urologic surgery. J Urol. 2009;181(3):1170-1177. doi: 10.1016/j.juro.2008.12.027.

Lin DW, Herr HW, Dalbagni G. Value of urethral wash cytology in the retained male urethra after radical cystoprostatectomy. J Urol. 2003;168(3):9610963. doi: 10.1097/01.ju.0000051907.16079.63.

Boorjian SA, Kim SP, Weight CJ, Cheville JC, Thapa P, Frank I. Risk factors and outcomes of urethral recurrence following radical cystectomy. Eur Urol. 2011;60(6):1266-1272. doi: 10.1016/j.eururo.2011.08.030.

A multidisciplinary set of guidelines for the treatment of patients with nonmetastatic muscle-invasive bladder cancer has been created as a result of a new collaboration between the American Urological Association and several other prominent urological groups.&nbsp;The new guidelines provide a risk-stratified clinical framework to better diagnose, treat, and manage the disease.&nbsp;

Multidisciplinary Guidelines for Diagnosis and Treatment of MIBC

&trade;, Jonathan E. Rosenberg, MD, discussed the guidelines and their significance for the treatment of patients with muscle-invasive bladder cancer (MIBC).

Rosenberg, a medical oncologist at Memorial Sloan Kettering Cancer Center, emphasized that one of the effects of these new guidelines is that cisplatin-based neoadjuvant chemotherapy prior to cystectomy is now being established among urologists as a standard of care for eligible patients. This treatment approach received a strong grade B recommendation in the guidelines and will improve survival for these patients.

Can you discuss these guidelines for bladder cancer and their significance?

Traditionally, MIBC has been managed purely by urologists in the United States with radical cystectomy being the only treatment often offered. However, there have been several large, randomized trials that show a benefit with cisplatin-based neoadjuvant chemotherapy prior to cystectomy.

There&rsquo;s been a large educational effort over the years, and this is an outgrowth of that effort to implement appropriate therapy for patients who are candidates for cisplatin-based neoadjuvant chemotherapy. We know that it reduces the risk of death from bladder cancer by one-third and improves the survival by 5% to 10%, depending on the clinical trial.

We have worked on these guidelines to establish this as a standard of care in conjunction with other organizations, such as ASCO. These guidelines now incorporate cisplatin-based chemotherapy for patients who have adequate kidney function, no significant neuropathy, no significant hearing loss, and who are otherwise healthy enough to undergo this type of treatment.

Is immunotherapy mentioned in these guidelines?

Not yet. Immunotherapy for these patients remains experimental, and there are multiple clinical trials that are testing this. There is a focus on adjuvant immunotherapy in large randomized phase III trials that are currently accruing patients. These trials are testing whether PD-1/PD-L1 inhibition versus observation or placebo, depending on the study, will improve survival for high-risk patients after cystectomy.

Postoperative treatment is generally adjuvant cisplatin-based chemotherapy for patients with high-risk disease who have not received neoadjuvant chemotherapy. In my opinion, if they have received neoadjuvant therapy, these patients should consider enrolling in one of these trials if their cancer is still high risk after cystectomy.

There are many patients who can&rsquo;t receive cisplatin-based chemotherapy for a variety of medical reasons, in which case they are not receiving neoadjuvant chemotherapy and could consider enrolling in one of the adjuvant therapy trials. To date, there are no results from these studies and we are looking for evidence that these patients would benefit from this approach.

: Have any recent advancements in the field affected these guidelines?

One of the questions that always arises is whether there are any molecular or clinical predictors about who would benefit from neoadjuvant chemotherapy. There are multiple intriguing technologies that are investigating this. My own opinion is that none of them are ready for primetime.

One methodology is looking at DNA damage-repair mutations, which is essentially the mechanism of action for cisplatin-based chemotherapy. It damages the DNA; the cells that have defective DNA repair are unable to recover, and we see better outcomes in those patients. However, the data thus far have been retrospective and it requires prospective validation.

There is also evidence for RNA-expression profiling. There is one subtype of bladder cancer, the basal subtype, that might benefit more from chemotherapy, although it doesn&rsquo;t mean that the other subtypes don&rsquo;t derive benefit. Work still needs to be done to better understand if that classifier can be used to select patients for chemotherapy, but it&rsquo;s not clear that they can tell someone that they don&rsquo;t need chemotherapy or that they wouldn&rsquo;t benefit from it.

That is all very exciting and interesting. There is a lot of intersection between that data, the outcomes of patients treated with immunotherapy, and advanced disease because many of the things that predict good responses to chemotherapy also predict good responses to immunotherapy. We are trying to integrate all of this knowledge to understand the potential novel targets that are responsible for these differences.

: How does having these guidelines benefit the treatment decisions for these patients?

Setting standards as to what is appropriate care is important in medicine and the care of patients with bladder cancer. We have a long history of failure to accrue to clinical trials, as well as a failure to follow guidelines for the treatment of these patients. Therefore, setting standards and guidelines will help to ensure that the recommendations are out there about how these matters should be handled.

An important area is bladder preservation, which is something that is involved in these guidelines with chemoradiation. There are 2 types of bladder preservation. The first is selective bladder preservation for people who could be cystectomy candidates but might do well with chemotherapy, radiation therapy, and radical transurethral resection. Or there are patients who also aren&rsquo;t candidates for cystectomy and need treatment for their MIBC. Those patients are also well served by chemoradiation as opposed to no treatment, which unfortunately often happens for many patients.

: What should the main takeaways be from these guidelines?

From a medical oncologist&rsquo;s perspective, the strong recommendation for perioperative systemic therapy is important because we know it cures patients. The problem is that we don&rsquo;t have a way to figure out who those patients are in advance. We need to select them so that we aren&rsquo;t treating everybody. We would rather only treat the patients who will benefit. At the moment, the data do support the use of these treatments. It is a major step forward to say that this is what is suggested as optimal therapy for these patients.

In an interview, Jonathan E. Rosenberg, MD, discusses the guidelines and their significance for the treatment of patients with muscle-invasive bladder cancer.

The Impact of the New Muscle-Invasive Bladder Cancer Guidelines

Germline mutations of BRCA 1/2 affect about 5% of patients with breast cancer and are associated with triple-negative breast cancer (TNBC), which has a poor prognosis and has been notoriously resistant to targeted therapies.

After more than a decade of development, poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors may offer these subgroups of patients an option &ldquo;that appears to be better in many ways than conventional chemotherapy,&rdquo; said Mark E. Robson, MD, a medical oncologist and clinical director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center.

Robson was lead investigator of the open-label phase III OLYMPIAD trial (NCT02000622) in which olaparib (Lynparza), an oral PARP inhibitor, was associated with a nearly 3-month improvement in median progression-free survival (PFS) compared with physician&rsquo;s choice of conventional single-agent chemotherapy in patients with heavily pretreated HER2-negative metastatic breast cancer and a confirmed or suspected germline BRCA mutation.

The median PFS was 7 months in the olaparib (300 mg twice daily) group and 4.2 months in the group that received 21-day cycles of either capecitabine (Xeloda), eribulin (Halaven), or vinorelbine (hazard ratio [HR], 0.58; 95% CI, 0.43-0.80; P <.001), Robson and his associates reported at the 2017 ASCO Annual Meeting.

The difference in this primary endpoint was slightly more striking among patients with TNBC (HR, 0.43; 95% CI, 0.29-0.63).

&ldquo;Inclusion of patients with TNBC in this study is important, given the limited treatment options for these patients after anthracyclines and taxanes,&rdquo; the investigators wrote when the findings were published simultaneously in the New England Journal of Medicine.

OLYMPIAD is the first of several phase III breast cancer trials of PARP inhibitors that &ldquo;hopefully will lead to FDA approvals and will be a promising option for women with BRCA mutations,&rdquo; Robson said. &ldquo;The question is whether we can improve the effectiveness of treatment in these women as well as in other populations of women with breast cancer, either through better selections or through biomarker analyses.&rdquo;

Results from OLYMPIAD cap more than a decade of work on PARP inhibition in ovarian, breast, and other cancers. Although the PARP enzyme family is involved in many cellular functions,

PARP-1 is the most abundant and best characterized for its vital role in repairing single-strand DNA breaks.

Based on this premise, investigators first developed PARP inhibitors to boost the cytotoxicity of chemotherapy and radiation.

By 2005, researchers found that BRCA 1/2-mutated cells from humans and mice were profoundly sensitive to PARP inhibitors, which triggered chromosomal instability, cell cycle arrest, and apoptosis.

These in vitro findings made sense, considering that the BRCA1 and BRCA2 proteins facilitate double-stranded DNA repair through the homologous recombination pathway, experts noted.

Deleterious BRCA mutations render cells deficient in BRCA proteins and are therefore unable to efficiently activate the homologous recombination apparatus. As a result, they rely on secondary PARP-dependent pathways to repair DNA damage.

By trapping PARP at the site of DNA damage repair, PARP inhibitors stall DNA replication and repair, ultimately leading to cytotoxic double-strand breaks in BRCA-deficient cells.

Inhibitors of PARP were first developed to treat BRCA-associated ovarian cancers, and work progressed rapidly in this setting.

By 2013, multiple phase III studies were enrolling patients, and by 2014, the FDA had approved olaparib as a third-line monotherapy for women with advanced ovarian cancer with confirmed or suspected germline BRCA mutations. Rucaparib (Rubraca) received a similar approval for ovarian cancer in 2016, and in 2017, the FDA approved both niraparib (Zejula) and olaparib oral tablets as maintenance therapies for recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who had a complete or partial response to platinum-based chemotherapy, regardless of BRCA status.

Olaparib tablets were also approved for the treatment of adult patients with deleterious or suspected germline BRCA-mutated advanced ovarian cancer who have received &ge;3 prior chemotherapy regimens.

BRCA mutations also play an important role in breast cancer, but trials in this setting have been slower to demonstrate the efficacy of PARP inhibition. Consider iniparib, the now-defunct investigational agent that showed promise in a phase II trial of patients with TNBC, but flopped in 3 phase III trials of patients with breast, ovarian, and squamous nonsmall cell lung cancers.

Experts concluded that iniparib did not strongly inhibit PARP and that the crossover design of the phase II trial might have biased the results toward the agent.

Aside from iniparib, the development of PARP inhibitors has been more difficult in breast cancer than in ovarian cancer, said Robson. He explained that most ovarian cancer trials of PARP inhibitors focused on maintenance therapy or enrolled women who had previously responded to a particular platinum-based chemotherapy treatment, which predicts response to PARP inhibition. &ldquo;In breast cancer, we don&rsquo;t usually treat that way,&rdquo; he said. &ldquo;Platinum has not been a commonly used agent, although that is changing. And in the United States, at least, the treatment of breast cancer tends to be ongoing until you move on to the next therapy.&rdquo;

Because the paradigm of maintenance therapy was uncommon in breast cancer, researchers had to compare PARP inhibitors head-to-head with chemotherapy, spurring extensive discussions about how best to do so, according to Robson. Breast cancer also might be more heterogeneous than ovarian cancer, he said. &ldquo;For example, in OLYMPIAD, half of patients were triple-negative and half were HER2-positive.&rdquo;

These challenges made OLYMPIAD&rsquo;s results noteworthy. Olaparib not only met the primary endpoint of PFS, but produced a higher response rate than chemotherapy (59.9% vs 28.8%) with a 36.6% risk of grade 3 or worse adverse events (AEs) compared with a 50.5% rate for chemotherapy.

The trial did not find a difference in overall survival (OS) between the groups, but it was not powered to do so. Moreover, patients in the chemotherapy group were more likely to receive PARP inhibitors, platinum-based treatment, or cytotoxic chemotherapy after disease progression, which could also confound analyses of this endpoint, the investigators noted.

Compared with chemotherapy, olaparib was also associated with a 7.5-point relative improvement (P = .004) in quality of life as measured by the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire.

&ldquo;Our formal definition of deterioration of quality of life was a 10-point drop in that instrument, and this was significantly delayed in people who received olaparib,&rdquo; Robson said. &ldquo;Olaparib was associated with fatigue, nausea, and anemia, but these were usually mild and did not lead to treatment discontinuation, whereas individuals who had chemotherapy had low blood cell counts and also developed hand-foot syndrome, or palmar-plantar erythrodysesthesia.&rdquo;

&ldquo;We see an improvement in PFS,&rdquo; said Robson of OLYMPIAD&rsquo;s major takeaways. &ldquo;Whether there&rsquo;s also an improvement in OS remains to be seen, but it did appear that the therapy was less toxic in several ways than conventional chemotherapy and women&rsquo;s quality of life was preserved for a longer period.&rdquo;&nbsp;

Many more trials are underway that should help address remaining questions about PARP inhibitors in breast cancer, Robson said. Ongoing studies are comparing conventional chemotherapy versus combination therapy with PARP inhibitors plus other agents that target DNA damage repair pathways (TABLE).

Moving forward, additional studies are assessing olaparib as maintenance therapy after platinum-based treatment of breast cancer and are also studying PARP inhibitors in combination with immune checkpoint inhibitors.

For the time being, OLYMPIAD provides the most promising data on PARP inhibitors in breast cancer, said Allison W. Kurian, MD, MSc, a medical oncologist and associate professor of oncology and health research and policy at Stanford University Medical Center. Among phase III trials of PARP inhibitors in breast cancer with readouts to date, only OLYMPIAD has met its primary endpoint.

The oral investigational PARP inhibitor veliparib (ABT-888) fell flat in a phase III placebo-controlled trial (NCT02032277) of patients receiving standard neoadjuvant therapy for early-stage TNBC, investigators reported at the 2017 ASCO Annual Meeting. Adding veliparib to carboplatin and paclitaxel did not significantly improve the rate of pathological complete response (53.2% vs 57.5% with placebo; P = .36).

Veliparib also did not significantly improve median PFS when added to paclitaxel and carboplatin in the placebo-controlled phase II BROCADE trial (14.1 vs 12.3 months with placebo; HR, 0.79; 95% CI, 0.54-1.16; P = .231).

Results from the phase III sister trial (BROCADE-3; NCT02163694) in patients with HER2-negative metastatic or locally advanced unresectable BRCA-associated breast cancer are expected in 2018.

Kurian is especially &ldquo;eager to see results of the phase III EMBRACA trial, which is investigating the PARP inhibitor talazoparib in BRCA 1/2 mutation carriers with metastatic breast cancer,&rdquo; she said. EMBRACA (NCT01945775) uses the same study design as OLYMPIAD, comparing the oral investigational PARP inhibitor with physician&rsquo;s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.

&ldquo;Using the same design as OLYMPIAD will be useful because it hopefully will confirm the results of OLYMPIAD with a different drug,&rdquo; said Robson. The trial also has enrolled more patients than OLYMPIAD, which might better power it to detect a difference in OS, he added.

The associated phase II trial (ABRAZO; NCT02034916) evaluated talazoparib (1 mg/day; 21-day cycles) in 70 patients with locally advanced or metastatic breast cancer with BRCA mutations who either had responded to platinum-based treatment or had received at least 2 prior lines of nonplatinum chemotherapy. The objective response rate was 24% in patients with BRCA1 mutations, 34% in patients with BRCA2 mutations, 26% in women with TNBC, and 29% in women with HER2-positive disease.

As with olaparib, the most common AEs included anemia (52%), fatigue (45%), and nausea (42%).

Robson and Kurian are both anticipating the results of the phase III placebo-controlled OlympiA trial (NCT02032823), which is evaluating olaparib as adjuvant therapy for patients with early-stage germline BRCA 1/2-mutated HER2-negative breast cancer. Study investigators are still enrolling participants and intend to finish collecting data on the primary endpoint of invasive disease-free survival by 2020. Meanwhile, the phase II/ III PARTNER (NCT03150576) trial is evaluating whether adding olaparib to platinum-based therapy in the neoadjuvant setting is safe and improves the likelihood of complete pathological response at surgery in patients with TNBC or germline BRCA-mutated breast cancer.

Additionally, a phase I study determined that the combination of olaparib and cyclophosphamide was tolerable and produced antitumor activity in individuals with germline BRCA mutations and set a phase II recommended dose for the combination for further study.

Niraparib is also the subject of several studies. The phase III BRAVO trial (NCT01905592) is comparing this oral PARP inhibitor with physician&rsquo;s choice of chemotherapy in patients with HER2-negative, germline BRCA-mutated breast cancer. Earlier this year, the sponsor reported that enough patients had dropped out of the chemotherapy control arm that the trial would probably not support a registration.20 However, a phase I/II trial (NCT02657889) is recruiting patients with TNBC or ovarian cancer to study treatment with niraparib plus the antiPD-1 antibody pembrolizumab (Keytruda). Additional trials of niraparib in breast cancer are planned, but are not yet recruiting.&nbsp;

Work also continues on rucaparib, which is currently approved for the treatment of ovarian cancer in patients with somatic or germline BRCA mutations. The phase II RUBY trial (NCT02505048) is evaluating rucaparib monotherapy (600 mg twice daily in 21-day cycles) in patients with HER2-negative breast cancer and mutations of BRCA 1/2 or other genes involved in the homologous recombination repair pathway.

Topline results are expected in December 2017.

For now, it&rsquo;s too soon to say which PARP inhibitors or combinations will provide the most benefit in breast cancer, or in which patient subgroups, Robson said. &ldquo;Even in ovarian cancer, this is not clear, and it would be difficult to extrapolate from ovarian cancer to breast cancer anyway. There are material differences between the drugs, and I&rsquo;m not sure there&rsquo;s a winner to pick in terms of the best agent.&rdquo;

He emphasized that increasing numbers of patients with breast cancer are being found to have either germline or somatic BRCA mutations or mutations in other genes in the homologous recombination pathway. For example, in a recent study of 560 patients with breast cancer, investigators identified all possible mutations and developed a weighted computer model called HRDetect that detected &ldquo;mutational signatures&rdquo;somatic substitutions and patterns of DNA insertions, deletions, and rearrangement corresponding with BRCA 1/2 mutations.

Only 22 patients (4%) in the cohort had known germline BRCA 1/2 mutations, which echoes the prevalence in other studies. Strikingly, HRDetect identified 22 additional tumors with somatic BRCA mutations and 47 tumors with a functional BRCA1/BRCA2 deficiency. None of these patients had detectible BRCA germline mutations. The researchers validated HRDetect in separate groups of patients with breast, ovarian, and pancreatic cancers, where it again detected tumors with &ldquo;BRCAness&rdquo; in patients who lacked the classic germline mutations.

Testing for these mutational signatures could help physicians identify patients whose breast cancer might be sensitive to PARP inhibition even though they lack BRCA 1/2 germline mutations, the researchers concluded. Editors of the September 2017 issue of Cancer agreed, noting that up to 20% of breast cancers might be treatable with PARP inhibitors if these findings hold up in other studies.

Kurian looks even further ahead. Five to 10 years from now, she hopes that additional trials will have spurred FDA approvals of PARP inhibitors that effectively treat BRCA 1/2-associated breast cancer, both in the metastatic and early-stage, curable settings, she said. &ldquo;I also hope that we will see efficacy of PARP inhibitors among patients whose breast cancers are the result of DNA repair gene mutations other than BRCA 1/2, such as ATM [ataxia telangiectasia mutated], for which we now routinely test in clinical practice.&rdquo;

Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13(11):674-690. doi: 10.1038/nrclinonc.2016.66.

Robson M, Im S-A, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. New Engl J Med. 2017;377(6):523-533. doi: 10.1056/NEJMoa1706450.

Robson ME, IM S-A, Senkus E, et al. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). J Clin Oncol. 2017;35(suppl 18; abstr LBA4). ascopubs.org/doi/ abs/10.1200/JCO.2017.35.18_suppl.LBA4.

Livraghi L, Garber JE. PARP inhibitors in the management of breast cancer: current data and future prospects. BMC Med. 2015;13:188. doi: 10.1186/s12916-015-0425-1.

Benanif S, Hall M. An update on PARP inhibitors for the treatment of cancer. Onco Targets Ther. 2015;8:519-528. doi: 10.2147/OTT.S30793.

Calabrese CR, Almassy R, Barton S, et al. Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 2004;96(1):56-67. doi: 10.1093/jnci/djh005.

Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. doi: 10.1038/nature03445.

Liu JF, Konstantinopoulos PA, Matulonis UA. PARP inhibitors in ovarian cancer: current status and future promise. Gynecol Oncol. 2014;133(2):362-369. doi: 10.1016/j.ygyno.2014.02.039.

Ali R, Rakha EA, Madhusudan S, Bryant HE. DNA damage repair in breast cancer and its therapeutic implications. Pathology. 2017;49(2):156-165. doi: 10.1016/j.pathol.2016.11.002.

Lim JSJ, Tan DSP. Understanding resistance mechanisms and expanding the therapeutic utility of PARP inhibitors. Cancers (Basel). 2017;9(8). pii: E109. doi: 10.3390/cancers9080109.

FDA approves maintenance treatment for recurrent epithelial ovarian, fallopian tube or primary peritoneal cancers [press release]. Silver Spring, MD: FDA; March 29, 2017. www.fda.gov/newsevents/ newsroom/pressannouncements/ucm548948.htm. Accessed September 14, 2017.

FDA approves olaparib tablets for maintenance treatment in ovarian cancer [press release]. Silver Spring, MD: FDA; August 17, 2017. www.fda.gov/drugs/informationondrugs/approveddrugs/ ucm572143.htm. Accessed September 14, 2017.

Sinha G. Downfall of iniparib: a PARP inhibitor that doesn&rsquo;t inhibit PARP after all. J Natl Cancer Inst. 2014;106(1):djt447. doi: 10.1093/jnci/djt447.

Robert M, Frenel JS, Gourmelon C, Patsouris A, Augereau P, Campone M. Olaparib for the treatment of breast cancer. Expert Opin Investig Drugs. 2017;26(6):751-759. doi: 10.1080/13543784.2017.1318847. 15. Geyer CE, O&rsquo;Shaughnessy J, Untch M, et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol. 2017;35(suppl 15; abstr 520). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.520.

Geyer CE, O&rsquo;Shaughnessy J, Untch M, et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J Clin Oncol. 2017;35(suppl 15; abstr 520). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.520.

Gampenrieder SP, Rinnerthaler G, Greil R. SABCS 2016: systemic therapy for metastatic breast cancer. Memo. 2017;10(2):86-89. doi: 10.1007/s12254-017-0326-4.

Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib (TALA) following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with germline BRCA 1/2 mutations (ABRAZO). J Clin Oncol. 2017;35(suppl 15; abstr 1007). ascopubs.org/doi/ abs/10.1200/JCO.2017.35.15_suppl.1007.

Earl HM, Vallier A-L, Qian W, et al. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. J Clin Oncol. 2017;35(suppl 15; abstr TPS591). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.TPS591.

Lee CK, Scott CL, Lindeman GJ, et al; Australia and New Zealand Breast Cancer Trials Group. Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA). J Clin Oncol. 2017;35(suppl 15; abstr 1104). ascopubs.org/doi/abs/10.1200/ JCO.2017.35.15_suppl.1104.

TESARO announces expanded development program for niraparib focused on the treatment of front-line metastatic ovarian and lung cancers and metastatic breast cancer [press release]. Waltham, MA: Tesaro; March 27, 2017. globenewswire.com/news-release/2017/03/27/945563/0/ en/TESARO-Announces-Expanded-Development-Program-for-Niraparib-Focused-on-the-Treatment- of-Front-Line-Metastatic-Ovarian-and-Lung-Cancers-and-Metastatic-Breast-Cancer.html. Accessed September 11, 2017.

Patsouris A, Vicier C, Campion L, et al. An open-label, phase II study of rucaparib, a PARP inhibitor, in HER2- metastatic breast cancer patients with high genomic loss of heterozygosity: RUBY. J Clin Oncol. 2017;35(suppl 15; abstr TPS1117). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_ suppl.TPS1117.

Davies H, Glodzik D, Morganella S, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med. 2017;23(4):517-525. doi: 10.1038/nm.4292.

More breast cancer patients could benefit from PARP inhibitors. Cancer. 2017;123(18):3433. doi: 10.1002/cncr.30962.

Mark E. Robson, MD, discusses the progress that has been seen in breast cancer care with the use of PARP inhibitors.

Select Ongoing Clinical Trials of PARP Inhibitors in Breast Cancer

Amultihistology basket study proved the targetability of the

mutation in human cancers by treating patients with various types of cancer harboring an

mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the

The PI3K/AKT pathway is one of the most frequently activated pathways across cancers and can be triggered by one of several mutations.

mutation can be found in many cancer types, they nonetheless occur at a relatively low prevalence in individual tumor lineages despite being the most common

mutation. The oncogenic nature of these gain-of-function mutations means they can be targeted with an AKT inhibitor in the hopes of improving patient outcomes.

The safety and efficacy of the AKT inhibitor had previously been investigated in patients with

-mutant estrogen receptor (ER)-positive breast cancer, HER2-positive breast cancer, or gynecologic cancers. Three of 51 patients experienced a partial response, and the optimal dose and schedule for AZD5363 was set.

mutations, 58 heavily pretreated patients were enrolled to receive 480 mg twice daily of AZD5363 on a 21-day cycle for 4 days followed by 3 days off, repeated weekly.

Of the enrolled patients, 52 showed expression of an E17K mutation, 2 patients had an

mutation; one patient had an undetectable mutation. Patients were a median 59 years (range, 31-77) and had received a median of 5 treatment regimens (range, 1-14). A majority of the patients (91.4%) were female and had a WHO performance status of 1 (53.4%); the remainder had a performance status of 0.

Following enrollment, patients were divided into 3 cohorts based on the location of their primary tumor: ER-positive breast cancer (n = 20), gynecologic cancers (n = 18), and other solid tumors (n = 20) (Table).

Table. Primary tumor location of enrolled patients

Once treatment commenced, patient disease was assessed and analyzed at baseline, every 6 weeks for 6 months, then every 12 weeks until any occurrence of a significant change in progression or withdrawal. The primary endpoint of this study was safety; response according to RECIST v1.1 criteria and progression-free survival (PFS) were key secondary endpoints.

Partial responses were confirmed in AKT1 E17K-mutant patients, including in 4 patients with ER-positive breast cancer, 2 with endometrial cancer, and 1 patient each with cervical cancer, triple-negative breast cancer, and lung adenocarcinoma. One patient with ovarian cancer with a Q17K mutation experienced stable disease and tumor regression lasting 14 months.

In treated patients with E17K mutations, the median

PFS was 5.5 months (95% CI, 2.9-6.9) for patients with ER-positive breast cancer, 6.6 months (95% CI, 1.5-8.3) for gynecologic cancers, and 4.2 months (95% CI, 2.1-12.8) for other solid tumor types. Researchers concluded that there was no apparent correlation between tumor type and response.

Grade &ge;3 adverse events (AEs) were observed in 70.7% of patients, and 51.7% were deemed to have a casually related AE, as assessed by the investigator. Hyperglycemia (24.1%), diarrhea (17.2%), and maculopapular rash (15.5%) were the common grade &ge;3 AEs reported. A dose reduction was necessitated in 34% of patients, with the above AEs being the leading causes. Serious AEs were experienced by 15.5% of patients, and the authors, led by David M. Hyman, MD, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, noted that the toxicity profile was consistent with that of previous studies with AZD5363.

Prior to treatment, researchers collected and sequenced tumor samples and tumor-derived cell-free DNA (cfDNA) for retrospective and comparative analysis purposes and to see whether response could be predicted through examination of biomarkers. Interestingly, in 1 evaluable sample in which the

mutation could not be confirmed in either cfDNA or archival tumor, the patient experienced rapid disease progression.

During cycle 1, a &ge;50% decrease in the

mutant allele in cfDNA was observed in 22 of 23 patients (95.5%) that showed no correlation with response. Observations of an ongoing decrease in mutant alleles going into cycle 2 showed an association with an increase in PFS (median PFS, 5.6 vs 2.6 months in those who did not demonstrate a decline; HR, 0.18;

= .004). Five patients experienced a clearance of

mutant alleles in cfDNA lasting more than 21 days that correlated with objective responses lasting &ge;18 weeks (

Through whole-exome or targeted sequencing in a smaller population of patients (n = 37), researchers tested to see if there was a correlation between the genomic configuration of the mutation and response to AZD5363. An allelic imbalance of

was observed in 57% of the tested patients (n = 21). Further testing revealed that 10 of these patients exhibited a copy-neutral loss of heterozygosity (CN-LOH), whereby 1 patient had acquired 2 copies of a mutant AKT1 E17K allele with no remaining wild-type allele. The authors noted that those patients experienced a longer PFS than those who did not exhibit CN-LOH (median PFS, 8.2 vs 4.1 months, respectively; HR, 0.41;

= .04), and they found this association to be clinically and statistically significant. Furthermore, they concluded that this E17K allelic imbalance was more commonly found in patients with breast or gynecologic cancers (90% vs 10% of other tumor types).

Clonality, or degree of tumor cell presence, of the

mutation may have some type of correlation with respones to AZD5363. Although 92% of patients (34 of 37) had

mutations present in all tumor cells, 2 of the remaining 3 patients with subclonal mutations exhibited a rapid increase in disease progression, and the third patient, who had ovarian granulosa cell cancer, experienced a mixed response. Hyman and his colleagues suspected that the third patient&rsquo;s overall tumor regression of 24% that lasted 253 days was caused by the later acquisition of the

driver mutation, which led to a response from treatment.

Amultihistology basket study proved the targetability of the AKT1 E17K mutation in human cancers by treating patients with various types of cancer harboring an AKT1 E17K mutation with AZD5363, an oral pan-AKT inhibitor, according to findings published in the Journal of Clinical Oncology.

October 2017

Predictive and Prognostic Biomarkers Sought in HCC

FGFR4 Inhibitor Demonstrates Promising Activity in HCC Subgroup

Multidisciplinary Guidelines for Diagnosis and Treatment of MIBC

The Impact of the New Muscle-Invasive Bladder Cancer Guidelines

Select Ongoing Clinical Trials of PARP Inhibitors in Breast Cancer

Study Shows AKT1 E17K a Targetable Mutation Through AKT Inhibition Across Various Cancer Types

Overview of Merkel Cell Carcinoma