Ariela Katz

The FDA has granted the PARP inhibitor Rubraca (rucaparib) a breakthrough therapy designation for single-agent use in adult patients with 

-positive metastatic castration-resistant prostate cancer (mCRPC) following at least one androgen receptor—directed therapy and taxane-based chemotherapy.

The designation, which will expedite the development and review of rucaparib in this setting, is based on initial data from the ongoing TRITON2 phase 2 study in advanced prostate cancer (

). Clovis Oncology, the manufacturer of the PARP inhibitor, reported in press release that the study data will be presented at the 2018 ESMO Congress.

“We hope the decision by the FDA to grant this breakthrough therapy designation for Rubraca offers encouragement to the prostate cancer community, and we will do our best to make Rubraca available to eligible prostate cancer patients as quickly as possible,” Patrick J. Mahaffy, President and CEO of Clovis Oncology, said in the press release.

The single-arm phase 2 TRITON2 study is enrolling men with mCRPC with germline or somatic 

1/2 mutations and evidence of a homologous recombination gene deficiency. Patients are unable to enroll if they previously received a PARP inhibitor, mitoxantrone, cyclophosphamide or any platinum-based chemotherapy. Individuals with symptomatic and/or untreated CNS metastases are also not eligible. The study is being conducted at 106 locations and the targeted enrollment is 160 patients.

The primary endpoints are objective response rate, and prostate-specific antigen (PSA) response. Secondary outcome measures include duration of response, radiologic progression-free survival, overall survival, clinical benefit rate, time to PSA progression and safety/tolerability. The estimated primary completion date is October 2019.

“We are pleased the FDA has granted breakthrough therapy designation to Rubraca in mCRPC,” Howard R. Soule, Ph.D., executive vice president and chief scientific officer of the Prostate Cancer Foundation, said in a statement. “There is tremendous need for new therapeutic options in advanced prostate cancer. In particular, we are enthusiastic about the potential for targeted therapies that may provide more meaningful benefit to patients with specific genetic mutations.”

Beyond TRITON2, the multicenter, randomized phase 2 TRITON3 clinical trial (

) is comparing single-agent rucaparib with physician’s choice of Zytiga (abiraterone acetate), Xtandi (enzalutamide) or Taxotere (docetaxel) in men with mCRPC and homologous recombination deficiency whose disease has progressed despite treatment with prior therapy.

Rucaparib has approved indications in ovarian cancer. Success with PARP inhibitors has spread to the field of breast cancer, and now, there is growing evidence of the efficacy of these agents in prostate cancer.

Celestia S. Higano, M.D., discussed emerging strategies to target PARP in prostate cancer during a presentation at the New York GUTM: 10th AnnualInterdisciplinary Prostate Cancer Congress® and other Genitourinary Malignancies conference, held by Physicians’ Education Resource

“PARP is an important mediator of DNA repair as the DNA strand breaks,” said Higano, a professor at the University of Washington School of Medicine and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center in Seattle. “And so, when we have a patient who has an underlying DNA repair problem and we inhibit PARP, we can end up with a situation where there is no DNA repair, leading to cell death.”

PARPs, a family of multifunctional enzymes, play a critical role in base excision repair, a process through which single-strand DNA breaks are mended. In her presentation, Higano identified other key repair pathways for different types of DNA damage: homologous recombination repair and nonhomologous end joining for double-strand breaks; nucleotide excision repair and translesion synthesis for bulky adducts; and mismatch repair for nucleotide mutations, substitutions, deletions and insertions.

In study results published in Cell in 2015, genomic testing of bone or soft tissue biopsies demonstrated that aberrations of 

were observed at substantially higher frequencies (19.3 percent overall) in advanced prostate cancer compared with those in primary prostate cancers.

The study also determined that the frequency of DNA repair alterations increases with disease progression.

Overall, the study found that 89 percent of affected individuals harbored a clinically actionable DNA aberration, including 62.7 percent with aberrations in the androgen receptor, 65 percent in other cancer-related genes and 8 percent with germline alterations.

Lynparza (olaparib), the first PARP inhibitor to gain the FDA’s approval in 2014 with an indication in recurrent ovarian cancer, is being investigated in prostate cancer under a breakthrough therapy designation based on phase 2 study data. In the trial, Lynparza demonstrated high response rates in patients with mCRPC and DNA repair defects.

The study enrolled 50 patients who were no longer responding to standard treatments, including docetaxel, Zytiga, Xtandi or Jevtana (cabazitaxel). Genomic sequencing was performed on tumor biopsies as a requirement of the study. Of the 49 evaluable patients, 16 (33 percent) had a response to the treatment with Lynparza, with 12 receiving the treatment for more than six months.

The study concluded that the presence of defects in DNA repair genes found in biopsies of metastatic tumors was associated with a high response rate to Lynparza in 14 of 16 patients, including all seven with loss of BRCA2.

“They didn’t really know this until after the study, but 14 out of the 16 responders had DNA repair alterations. This was a pretty small study, but it has prompted a lot of interest in researching PARP inhibitors in prostate cancers,” said Higano.

Articles

The FDA has granted the PARP inhibitor Rubraca (rucaparib) a breakthrough therapy designation for single-agent use in adult patients with BRCA1/2-positive metastatic castration-resistant prostate cancer (mCRPC) following at least one androgen receptor–directed therapy and taxane-based chemotherapy.
 

Rubraca Granted Breakthrough Designation for Prostate Cancer

When given neoadjuvant chemotherapy before getting a radical cystectomy, patients with the basal subtype of muscle-invasive bladder cancer (MIBC) saw significantly improved overall survival (OS) compared to those who had a cystectomy alone, according to a recent study.

In the study, OS was dramatically improved with neoadjuvant chemotherapy for patients with basal tumors, regardless of whether they had high-risk or low-risk MIBC. In a multivariate analysis correcting for age, male gender and stage, there was an 86.5 percent reduction in the risk of death with the addition of neoadjuvant chemotherapy compared with cystectomy alone for patients with the basal subtype. There was no survival advantage when looking at the luminal or p53-like subtypes with neoadjuvant chemotherapy.

“There was a significant survival advantage noted in basal tumors that received neoadjuvant chemotherapy. This held true in a multivariate analysis that was statistically significant,” Jonathan Duplisea, M.D., a urology fellow at the University of Texas MD Anderson Cancer Center, said during a presentation of the results. “In this particular cohort of patients, survival of low-risk patients is improved by neoadjuvant chemotherapy. This benefit appears to be confined to basal tumors.”

Neoadjuvant chemotherapy is known to play a role in the treatment of MIBC prior to cystectomy; however, widespread adoption of this treatment strategy has not occurred, with some papers finding that around 20 percent of patients end up getting neoadjuvant chemotherapy. Commonly cited reasons for this lack of adoption are concerns about the toxicity and not wanting to delay surgery.

The trial included 165 patients with MIBC who were treated with radical cystectomy with or without neoadjuvant chemotherapy at MD Anderson or the University of British Columbia. Patients were classified as high or low clinical risk, based on hydroureteronephrosis, clinical T3a to T4b disease, histologic evidence of lymphovascular invasion (LVI) and micropapillary or neuroendocrine features at the time of transurethral resection. Whole genome analysis was performed on transurethral resection specimens classifying them as luminal, basal, or p53-like.

Patients were a median age of 65 years (range, 35-89), with 68 percent classified as high risk and 32 percent as low risk. In terms of disease state and clinical features, 27 percent had T3b disease, LVI was identified in 21 percent of patients, hydroureteronephrosis in 29 percent and 16 percent had variant histology. There was relatively even distribution of the subtypes, with 30 percent basal, 39 percent p53-like and 31 percent luminal.

“Importantly, there were no differences in the subtypes with respect to age, sex and stage,” Duplisea noted.

Across all enrolled patients, there was a distinct OS advantaged in patients with clinically high-risk disease with neoadjuvant chemotherapy compared with radical cystectomy alone, with a 49 percent reduction in the risk of death in the neoadjuvant arm after more than 200 months of follow-up. Additionally, an improvement in OS was also seen with neoadjuvant chemotherapy in the low-risk population.

Looking at subtype and clinical risk stratification, in the high-risk patients with basal tumors, there was a distinct survival advantage, Duplisea noted. With nearly 300 months of follow-up, 25 percent of patients in the neoadjuvant chemotherapy arm remained alive versus none in the surgery-alone group. In the low-risk, basal population, 100 percent of patients who received neoadjuvant chemotherapy remained alive compared with approximately 20 percent of those who did not receive neoadjuvant therapy.

“If we did not know the subtypes of these patients, they would have been classified as low-risk, and not received chemotherapy using our risk-stratified approach,” Duplisea said. “Despite the small number that we had, once we dissected everything down in terms of risk stratification and subtype, we believe that the definition of high-risk should be emended to include the basal subtype,” he concluded.

Upfront Chemotherapy Improves Survival in Bladder Cancer Subtype

A NEW DRUG COMBINATION in testing could hit non-small cell lung cancer (NSCLC) with a one-two punch: simultaneously suffocating tumor cells and preventing new ones from forming.

Plinabulin, an angiogenesis inhibitor that prevents growth of new blood vessels, is being tested in combination with the chemotherapy drug Taxotere (docetaxel) as an option for patients with advanced stage 4 NSCLC who have progressed after treatment with standard-of-care therapy. The investigators intend to determine the overall survival (OS) benefit of plinabulin for patients receiving second- or third-line chemotherapy.

For patients treated solely with chemotherapy, OS is often very short, with a median survival of 7 to 8 months, according to Goetz H. Kloecker, M.D., M.S.P.H., MBA, FACP, an associate professor of medicine and director of the Thoracic Oncology and Hematology/Oncology Fellowship programs at the University of Louisville in Kentucky. “In the initial trials, [for patients who had] larger tumors — more than 3 centimeters &mdash; OS and progression-free survival (PFS) was significantly improved, and significant for lung cancer means the median survival was improved by more than 2 months. It may not sound like much, but for lung cancer, a median of 2 months often translates that there are more people alive 1 or 2 years later,” Kloecker said.

This drug could represent a big step forward in helping patients with lung cancer who have received standard-of-care therapies in the first- or second-line setting. There are currently two approved antiangiogenetic therapies for this patient population — Avastin (bevacizumab) and Cyramza (ramucirumab) &mdash; and adding another option to be combined with Taxotere could lead to treating more patients for a longer period.

“Tumors need a lot of blood, since they live on oxygen,” Kloecker said. “Plinabulin blocks blood vessels from growing and kills tumor blood vessels. It does this by blocking the inner microtubules of the blood vessels, killing them and depriving the tumor cells of oxygen, causing cell death.” Adding Taxotere, which blocks the mitosis of cancer cells, creates a “double hit” to the tumor’s system, he said, and the cancer cells can no longer replicate.

The combination thus targets the environment surrounding the cancer, the blood vessels and the cells all at the same time. “Combining standard docetaxel with something that brings more punch, like blocking the blood vessels, makes sense,” Kloecker said. “You suffocate the cancer cells because there is no oxygen, and you make them stop replicating with the chemotherapy.”

The trial will randomize approximately 550 participants to receive either the combination of plinabulin and Taxotere, or Taxotere alone with a placebo. Eligible patients will have metastatic, stage 4 NSCLC and have progressed after initial treatment with standard therapy, including chemotherapy or immunotherapy, with no severe heart problems or brain metastases. Patients also must have an Eastern Cooperative Oncology Group performance status of zero to 2, and at least one lesion larger than 3 centimeters in diameter in the lung parenchyma. Since it is a large phase 3 trial, the investigators will be assessing OS, PFS and duration of response (DoR).

In a previous phase 2 study of plinabulin and Taxotere in patients with advanced NSCLC, the median OS was 11.3 months, with a PFS of 3.7 months, compared with 6.7 months and 2.9 months, respectively, with Taxotere alone. The DoR of the combination was 12.7 months versus 1 month. The investigators concluded that adding plinabulin to Taxotere improves the efficacy versus Taxotere alone.

The two drugs do not have overlapping toxicities or side effects and it tends to be well tolerated.

Notably, lesion size does seem to matter in terms of plinabulin’s efficacy.

Although this drug is not a “sure thing,” Kloecker said, he added that patients tend to do better when enrolled in clinical trials and encourages people with NSCLC to ask their physicians if a trial center is near their area. U.S. trial locations are in California, Colorado, Georgia, Illinois, Kentucky, Mississippi, Ohio and Tennessee. The majority of the enrollment is taking place in China.

For patients with advanced disease, median survival was improved.

Novel Drug Combination Hits Non-Small Cell Lung Cancer With Double Punch

A NOVEL ANTIBODY-DRUG conjugate is being investigated as a single-agent treatment for patients with advanced, platinum-resistant epithelial ovarian cancer that expresses a certain protein, in an effort to provide an effective option for a population facing a difficult prognosis.

The drug is mirvetuximab soravtansine (IMGN853), and the phase 3 FORWARD 1 trial is testing it in patients whose cancers have medium to high expression levels of the protein folate receptor—alpha (FR-alpha).

That’s because the drug targets FR-alpha, a cell-surface glycoprotein found on approximately 80 percent of epithelial ovarian cancer tumors; its overexpression may be associated with negative outcomes in patients treated with chemotherapy. The study also includes women with primary peritoneal and fallopian tube cancers that express the protein.

If successful, the novel drug would offer an alternative to patients who have not responded to platinum-based chemotherapy, and possibly to individuals who have become resistant to chemotherapy.

“This would be another agent available for patients with platinum-resistant disease, for which, outside of combination chemotherapy and Avastin (bevacizumab), there are really no therapies with an expected response rate,” said Kathleen N. Moore, M.D., associate director for clinical research and director of the TSET Phase I Drug Development Unit at the Stephenson Cancer Center in Oklahoma, and a co-principal investigator on the study.

“If they can’t get bevacizumab — which a lot of patients can’t (due to issues such as risk factors for cardiac or gastrointestinal side effects) &mdash; then this may be their first line in platinum-resistant cancer. It gives another, better option with a higher chance of working over a longer period of time without as many adverse effects. It moves up the line in terms of options for patients with platinum-resistant ovarian cancer,” she added.

It is estimated that 23,000 women are diagnosed annually with ovarian cancer in the U.S. Patients with ovarian cancer who are also resistant to platinum-containing chemotherapy comprise a population with an unmet need, as they are difficult to treat and they need more options after first- and second-line therapy.

) is currently enrolling patients at 79 locations, including many in the United States. It seeks to randomize 333 women in a 2:1 ratio to either the experimental mirvetuximab soravtansine arm or to chemotherapy consisting of investigator’s choice of paclitaxel, pegylated liposomal doxorubicin or topotecan. Eligible patients will have advanced epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer with FR-alpha-positive tumor expression. Patients must also have platinumresistant disease, and must have received at least one, but no more than three, prior treatments. Patients with low-grade ovarian cancer or clear-cell ovarian cancer are not eligible, mainly because the investigators don’t think they will get any benefit from the therapy.

Mirvetuximab soravtansine acts like a “targeted bomb,” according to Moore, that is programmed to target FR-alpha and carries very potent molecules of chemotherapy that are very dissimilar to anything the patients will have previously received. The chemotherapy is going directly to the cancer cells, instead of to the whole body, as with typical systemic chemotherapy, which goes wherever there is a blood vessel.

The cancer cell accepts the drug into the cell, like a Trojan horse, and when the medicine gets there, it releases its payload of chemotherapy and the cell dies. The chemotherapy molecules can then disperse to other cells locally and infect them, as well.

Although the drug is generally well tolerated, one of its most common side effects is low-grade diarrhea in 30 to 40 percent of patients, according to Moore. Like other antibody— drug conjugates, the drug can also cause keratopathy, damage to the limbus of the cornea that causes transient blurry vision and is observed in about 10 percent of patients. Because preventing dry eyes often prevents keratopathy, lubricating eyedrops are mandatory in the study.

Should keratopathy occur, persist or become more severe, the dose of the drug is either lowered or withheld entirely, and patients can resume the treatment after it’s resolved. Due to this risk, any patients who have a history of corneal abnormalities, which Moore noted is uncommon, will be excluded from the study.

According to a pooled analysis of phase 1 expansion cohorts that was presented at the 2017 Annual Meeting of the American Society of Clinical Oncology, mirvetuximab soravtansine demonstrated a favorable toxicity profile and encouraging clinical activity. “The early-phase data is very strong in terms of the response rate and the duration of response, as well as the tolerability of the drug, so we are excited to move this drug into the marketplace, and we hope patients are excited about it,” Moore said.

There were 113 patients with epithelial ovarian cancer in the pooled analysis, including a cohort of 36 patients who met the inclusion criteria for FORWARD I. In all pooled patients from the phase 1 analysis, the confirmed overall response rate (ORR) was 30 percent, and included three complete responses and 31 partial responses. The confirmed ORR was 47 percent in the group eligible for FORWARD I, including one complete response and 16 partial responses.

“It was a good opportunity to look at a large number of patients who have been treated with the drug, then to try to narrow it down to the population who benefited the most, and that was the population that had three prior regimens and medium to high expression,” said Moore. “That’s not to say other groups don’t benefit at all; someday we may go back and look at this in other populations, in lower expressers in different histologies.”

There seems to be a lot of promise for the drug, and it is under investigation in other settings, as well. “There are several phase I studies running in combination with a number of chemotherapies, as well as with pembrolizumab (Keytruda) and bevacizumab,” Moore said.

Mirvetuximab soravtansine is being developed by ImmunoGen.

An antibody–drug conjugate is being tested in patients with platinum-resistant ovarian cancer.

Ariela Katz

Rubraca Granted Breakthrough Designation for Prostate Cancer

Upfront Chemotherapy Improves Survival in Bladder Cancer Subtype

Novel Drug Combination Hits Non-Small Cell Lung Cancer With Double Punch

New Options Are Being Explored in Ovarian Cancer

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