Angelica Welch

The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for Lynparza (olaparib) tablets for use as a maintenance therapy in patients with newly-diagnosed,

-positive advanced ovarian cancer who achieved a complete or partial response to standard frontline platinum-based chemotherapy.

The sNDA is based on data from the phase 3 SOLO-1 trial, in which the PARP inhibitor Lynparza significantly improved progression-free survival (PFS) as frontline maintenance for this patient population. With a median follow-up of 41 months, the median PFS by independent central review was not reached in the Lynparza arm (260 patients), versus 14.1 months in the placebo arm (131 patients). The investigator-assessed PFS in the Lynparza arm was not reached, compared to 13.8 months in the placebo arm.

At 36 months, the PFS rate was 60 percent in the Lynparza group versus 27 percent in the placebo arm. According to AstraZeneca and Merck (MSD), the codevelopers of Lynparza, the FDA action date for the sNDA is set for the first quarter of 2019.

) evaluated maintenance Lynparza following platinum-based chemotherapy in newly-diagnosed patients with advanced ovarian cancer with a 

 mutation. Patients with newly diagnosed, FIGO stage 3-4, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer with germline or somatic 

 mutations were enrolled. These patients must have also received cytoreductive surgery, and be in clinical complete response or partial response after platinum-based chemotherapy.

The study treatment in SOLO-1 continued until disease progression, and treatment was ceased for patients with no evidence of disease at two years. Although, patients with a partial response at two years could continue treatment.

Secondary endpoints of the trial were PFS2, which is defined as time from randomization to second progression event, overall survival, and quality of life.

Patients who received Lynparza maintenance showed a statically significant improvement in PFS2, with a median PFS2 not reached, compared with 41.9 months in the placebo group. Overall survival data are not yet mature. Regarding quality of life, there were no clinically relevant changes. The discontinuation rate in the Lynparza arm was 12 percent.

“It is estimated that over 50 percent of women on the olaparib arm were still progression free at four years as compared to only 11 percent for placebo,” Kathleen Moore, M.D., principal investigator of SOLO-1, said when presented the data at the 2018 ESMO Congress.

“A key point here is that there was no change in the Kaplan-Meier curve at the two-year mark when we stopped the olaparib or placebo therapy. So, it appears that the benefit of olaparib maintenance is extended beyond even the two-year timepoint in which patients were receiving treatment,” added Moore, an associate professor at Stephenson Cancer Center, University of Oklahoma.  

Adverse events (AEs) observed were low-grade, with the most common grade 3 or higher AEs in the Lynparza arm being anemia (22 percent) and neutropenia (8 percent). Baseline characteristics, including health-related quality-of-life scores, were balanced between the two arms.

“While ovarian cancer is a highly treatable disease due in large part to its exquisite chemosensitivity, the percentage of patients who survive disease-free for long periods of time is dismally low, and hovers in the 10 percent to 15 percent range,” said Moore. “If we are going to make meaningful improvements on that rate, it has to be with improvements in frontline treatment.”

The majority of patients with ovarian cancer recur within three years of diagnosis, Moore said. Although their disease has the potential to be treated, those patients are no longer considered treatable. Moore emphasized the importance of SOLO-1, as it is the first phase 3 large prospective data set for this population of women.

Lynparza is currently FDA approved for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of 

mutation status, and for the treatment of advanced ovarian cancer patients with a germline 

 mutation previously treated with three or more lines of chemotherapy.

A version of this article originally appeared on 

FDA Grants Olaparib Priority Review for Frontline Maintenance in Ovarian Cancer.

Articles

The FDA has granted a priority review designation to a supplemental new drug application (sNDA) for Lynparza (olaparib) tablets for use as a maintenance therapy in patients with newly-diagnosed, BRCA-positive advanced ovarian cancer who achieved a complete or partial response to standard frontline platinum-based chemotherapy.
 

FDA Grants Lynparza Priority Review for Frontline Maintenance in Ovarian Cancer

A NEW CLASS OF drugs for patients with hormone-driven breast cancer has generated additional therapeutic options, including more combination therapies. That’s the basis for excitement around the Food and Drug Administration’s approval of three cyclin-dependent kinase (CDK) 4/6 inhibitors in the last three years, according to Jacqueline Vuky, M.D.

Vuky, an associate professor of medicine at the Oregon Health and Science University School of Medicine, discussed the management of metastatic breast cancer with CDK4/6 inhibitors during an interview at the 2018 

® State of the Science Summit™ on Breast Cancer.

During her talk at the summit, Vuky gave an overview of the three drugs: Ibrance (palbociclib), Kisqali (ribociclib) and Verzenio (abemaciclib). They interfere with the activity of the enzymes CDK4 and CDK6, thus preventing cancer cells from dividing or multiplying. Each drug was approved for use in combination with an aromatase inhibitor (AI) as initial treatment for postmenopausal women whose metastatic cancers are fueled by the hormones estrogen or progesterone, but not by the protein HER2. AIs work by preventing the body’s natural production of estrogen.

In clinical trials, the CDK4/6 inhibitors sparked an improvement in progression-free survival (PFS) — the time until disease grows &mdash; but did not increase length of life. When added to AIs, they led to better outcomes for all eligible patients.

®: Can you share the highlights of your presentation on CDK4/6 inhibitors?

Vuky: CDK4/6 inhibitors are very exciting. We haven’t had a breakthrough with endocrine (hormonal) therapy for metastatic disease or even early-stage disease for a while. For a long time now, we have been trying combinations with endocrine therapy and therapeutic targets. The fact that this is the first combination that has changed median PFS is very exciting for our patients. Giving them more options is why we do clinical research.

How do multiple approvals of CDK4/6 inhibitors affect treatment? 

Much like with other targeted therapies, such as mTOR inhibitors, it is exciting that we have choices, but it does seem that each one is a little different. Although the data show similar efficacy, as well as improvement in median PFS, compared with the standard therapy, each differs in side effects and schedules, and even abilities to bind to CDK4 or 6. We like choices, although we do have to be concerned about the price of all of these drugs and the added side effects compared with AI therapy alone.

If a patient’s disease progresses on a CDK4/6 inhibitor, is there rationale to move them to another?

There are no data yet. We need and would like to have data to inform us and our patients on the effectiveness of this strategy. Since abemaciclib is approved as a single agent and has stronger affinity for CDK6 as opposed to CDK4, there has been discussion that it’s reasonable to consider switching to this drug after progressing on palbociclib or ribociclib (although the study that led to its approval did not include any patients who had progressed on another CDK4/6 inhibitor.)

A very interesting trial is looking at adding a CDK4/6 inhibitor to an AI in patients whose disease is starting to progress. I find that fascinating, and these questions need to be answered.

What are your thoughts on combinations with CDK4/6 inhibitors?

There are some triplet combinations that may overcome resistance to endocrine therapy. We participated in a combination of Kisqali, the mTOR inhibitor Afinitor (everolimus) and the AI Aromasin (exemestane). At least in our patients, it was really well tolerated.

What about the potential of Verzenio plus the immunotherapy Keytruda (pembrolizumab)?

Lilly Oncology has some information on that preclinical data, as well as the neoMONARCH trial, which is the presurgical trial where they looked at Verzenio as a way to prime tumor cells for immune recognition. Results from a phase 1 trial with Verzenio plus Keytruda, an immune checkpoint inhibitor, were presented in December 2017. (The findings suggested the combination sparked responses in some patients with hormone-driven metastatic breast cancer without worsening side effects.)

(For HER2-positive cancers), there are trials combining CDK 4/6 inhibitors plus anti-HER2 therapies such as Herceptin (trastuzumab) and Perjeta (pertuzumab), as well.

Do you have any advice for patients and their physicians who are deciding between agents?

First, I would ask whether the patient needs combination therapy versus AI therapy. We know that there is a subgroup of patients with a good prognosis who might do well with an aromatase inhibitor alone, although the exact way to define such patients remains unclear. Patients who have poor prognostic features, such as a short time from (post-treatment) endocrine therapy to relapse, might do better with combination therapy. That is the first question they have to ask: “Is combination or single-agent therapy better for my case?”

The second thing to do is look at the toxicities; if a patient has an erratic heartbeat or is on a drug to treat this, I would not give Kisqali. I do think there are some clinical judgments to make when looking at different toxicities and tailoring it for patients.

Three CDK4/6 inhibitors have been approved, offering new options to those with metastatic, hormone-driven breast cancer.

Good Things Come in Threes

The PARP inhibitor Lynparza (olaparib) significantly improved progression-free survival (PFS) as frontline maintenance therapy for women with 

-positive advanced ovarian cancer, according to findings from the randomized phase 3 SOLO-1 trial presented at the 2018 ESMO Congress.

With a median follow-up of 41 months, the median PFS by independent central review was not reached in the Lynparza arm (260 patients), versus 14.1 months in the placebo arm (131 patients). The investigator-assessed PFS in the Lynparza arm was not reached, compared to 13.8 months in the placebo arm. Although the median PFS for Lynparza has not yet been reached, Moore said that it looks to be an approximate three-year advantage over placebo.

"We feel that the SOLO-1 trial has demonstrated an unprecedented improvement in the progression-free survival in patients with a 

 mutation who have advanced ovarian cancer when olaparib is incorporated following platinum-based chemotherapy,” said Kathleen Moore, M.D., associate professor, Stephenson Cancer Center, University of Oklahoma, and principal investigator of SOLO-1, during a press conference at the meeting.

The ongoing SOLO-1 trial (NCT01844986) is evaluating maintenance Lynparza following platinum-based chemotherapy in newly-diagnosed patients with advanced ovarian cancer with a 

Patients who received Lynparza maintenance showed a statically significant improvement in PFS2, with a median PFS2 not reached, compared with 41.9 months in the placebo group. Overall survival data are not yet mature, noted Moore. Regarding quality of life, there were no clinically relevant changes. The discontinuation rate in the Lynparza arm was 12 percent.

“It is estimated that over 50 percent of women on the olaparib arm were still progression free at four years as compared to only 11 percent for placebo,” said Moore. “A key point here is that there was no change in the Kaplan-Meier curve at the 2-year mark when we stopped the olaparib or placebo therapy. So, it appears that the benefit of olaparib maintenance is extended beyond even the 2-year timepoint in which patients were receiving treatment.”

“While ovarian cancer is a highly treatable disease due in large part to its exquisite chemosensitivity, the percentage of patients who survive disease-free for long periods of time is dismally low, and hovers in the 10 percent to 15 percent range,” Moore noted. “If we are going to make meaningful improvements on that rate, it has to be with improvements in frontline treatment.”

“Maintenance olaparib should be considered standard treatment following platinum-based chemotherapy for women with newly diagnosed advanced ovarian cancer and a 

Additionally, panelists at the press conference suggested that the field should be looking to the possibility of extrapolating this data to other high-grade serous carcinomas.

Lynparza is not currently approved by the FDA as a first-line maintenance treatment for newly diagnosed patients with 

-positive ovarian cancer. The PARP inhibitor is FDA approved for the maintenance treatment of recurrent ovarian cancer in response to platinum-based chemotherapy regardless of 

A version of this article originally appeared on onclive.com with the title, "

Olaparib Substantially Improves PFS as Frontline Maintenance in Ovarian Cancer."

The PARP inhibitor Lynparza (olaparib) significantly improved progression-free survival (PFS) as frontline maintenance therapy for women with BRCA-positive advanced ovarian cancer, according to findings from the randomized phase 3 SOLO-1 trial presented at the 2018 ESMO Congress.

Maintenance Lynparza Improves PFS for Ovarian Cancer

For patients, one of the most worrisome side effects of treatment for bladder cancer may be the removal of the organ, making it necessary for doctors to create a urostomy, an opening in the body that drains urine into a bag.

That’s one reason for research considering ways to treat urothelial carcinoma, the most common type of bladder cancer, without removing the bladder in certain patients. The goal is to improve long-term quality of life without compromising oncologic outcomes, according to Amy N. Solan, M.D., an assistant professor in the department of radiation oncology at NYU Langone Health in New York City. Bladder preservation may be a reasonable approach for patients who are not candidates for surgical removal of the organ — a procedure known as cystectomy. This alternative approach is particularly appropriate for patients who are older or are current or former smokers. Furthermore, many patients would simply prefer the less invasive procedure, Solan said in a presentation at the 2018 OncLive® State of the Science Summit™ on Genitourinary Malignancies.

Quality of life was evaluated in an analysis of organ conservation in invasive bladder cancer through removal of just the tumor, chemotherapy and radiation. The analysis showed that most of the patients who kept their bladders maintained normal bladder function and had low rates of urinary incontinence and bowel symptoms.

Data on the safety and efficacy of bladder preservation have come from single-institution studies in the United States and Europe, as well as phase 2 trials from the Radiation Therapy Oncology Group. Although it is difficult to collect unbiased information, Solan said, bladder preservation outcomes in selected patients appear comparable with those of people who undergo organ removal, with half of patients or more surviving five years and about 70 percent of these patients maintaining an intact bladder during that time period.

Solan emphasized that patient selection is key when bladder preservation is being considered in surgical candidates. Those eligible have cancer that has grown into the bladder wall or the tissue surrounding the organ but not into lymph nodes. Although many studies include patients with disease that has spread further into the genitourinary tract, this group is often underrepresented, Solan said.

Patients who should not be considered for bladder preservation are those with diffuse, stage 0 disease that’s difficult to remove surgically; those whose cancer location makes more extensive surgery difficult; or those with hydronephrosis (kidney swelling due to inability to drain urine), a well-known indicator of a poor prognosis. A lack of sufficient study leaves questions about the eligibility of patients with rarer variations of bladder cancer: adenocarcinoma and squamous cell.

The current standard treatment for muscle-invasive bladder cancer is radical cystectomy, meaning the removal of the bladder and lymph nodes on both sides of the pelvis. Platinum-based chemotherapy and radiation are given before the surgery.

Although a number of trials have evaluated the role of chemotherapy, the order in which treatments are given, and radiotherapy volume or dosage, the optimal bladder-sparing approach has not been identified, Solan said.

In her presentation, she discussed bladder preservation accomplished by removing just the tumor, followed by chemoradiation.

This more minimal surgery is conducted via a scope inserted through the urethra.

Patients with additional medical conditions or poor renal function who want to preserve their bladders might benefit from regimens that include chemotherapies meant to sensitize the cancer to radiotherapy, such as capecitabine, paclitaxel, paclitaxel/ carboplatin, 5-fluorouracil/mitomycin C and gemcitabine, she said.

Another preservation approach involves temporarily stopping chemoradiation to allow for a cystoscopy, a test that checks the health of the bladder lining. Radiation Therapy Oncology Group trials have shown that, in 70 percent of patients, cytoscopy reveals a complete response to the initial courses of chemoradiation, an outcome associated with improved five-year disease-free survival, Solan noted.

However, midcourse cystoscopy has been a topic of debate. Proponents argue that an early cystoscopy lets clinicians identify patients who are not responders and refer them to salvage cystectomy. On the flip side, Solan said, other trials have shown that delaying part of the radiotherapy course decreases local cancer control rates.

Other preservation approaches include hypofractionation (large doses of radiation given over a relatively short time frame) and immunotherapy combined with radiation therapy. In addition, combination chemotherapy and radiation can be an alternative to bladder removal. A 2016 review of studies investigating this technique found that it generated “favorable disease-specific survival and bladder preservation rates,” according to its authors.

Following bladder preservation, 20 to 30 percent of patients will be found to have residual tumor when checked for restaging of their disease, and the same percentages of this group will develop new or recurrent disease in the bladder. Patients with muscleinvasive bladder cancer that resists treatment or has recurred will need to undergo a salvage cystectomy.

“It is important, when a patient is going to undergo bladder preservation, that they understand that salvage cystectomy may be a part of the equation,” Solan said.

Some patients eligible for bladder surgery due to cancer may safely opt to preserve the organ. 

Angelica Welch

FDA Grants Lynparza Priority Review for Frontline Maintenance in Ovarian Cancer

Good Things Come in Threes

Maintenance Lynparza Improves PFS for Ovarian Cancer

When Less Is More in Bladder Cancer Treatment

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