What to Know About Piqray (Alpelisib)

Piqray (alpelisib) is a medication for metastatic breast cancer that received approval by the U.S. Food and Drug Administration (FDA) on May 24, 2019. Taken as a daily tablet that is swallowed whole, this drug is used in combination with Faslodex (fulvestrant) for both postmenopausal women and men who have advanced hormone receptor-positive and HER2 negative breast cancer that has progressed on hormonal therapy and tests positive for a PIK3CA mutation. When used in this setting, the combination of Piqray and Faslodex almost doubled progression-free survival relative to the combination of Faslodex and a placebo alone. Common side effects include hyperglycemia (elevated blood sugar) and a rash, among others.

Uses

Among people who have metastatic hormone receptor-positive breast cancer, PIK3CA mutations are common (found in roughly 30% to 40% of people). Piqray inhibits the P13K protein coded for by the gene that is important in the growth of these cancers

As the first drug to be approved in this category, approval of Piqray adds another option besides chemotherapy that provides a significant advance in the treatment of metastatic breast cancer.

It is indicated for people who have already been treated and progressed on endocrine (hormonal) therapy such as tamoxifen or the aromatase inhibitors Arimidex (anastrozole), Aromasin (exemastane), or Femara (letrozole).

At the current time there are no off-label uses for Piqray.

Studies on Effectiveness and Discontinuation

Piqray was approved following a phase 3 clinical trial (SOLAR-1) published in 2019 in the New England Journal of Medicine. In this trial, the median progression-free survival for people treated with Piqray plus Faslodex was 11.0 months compared with 5.7 months in those treated with Faslodex plus a placebo.

The overall response rate to the drug in those who had measurable disease (cancer that could be seen and measured on testing) was 35.7% in the Piqray/Faslodex group and 16.2% in the Faslodex/placebo group. The rate of discontinuation of the drug due to adverse reactions was 25% in the Piqray/Faslodex group and 4.2% in the Faslodex/placebo group.

Previous P13K inhibitors (that inhibited all subunits of the enzyme) had been tested but were limited by toxicity. Piqray, in contrast to these medications, is a PI3Kα-specific inhibitor, and currently the only approved drug in this category.

Before Taking

Before prescribing Piqray, oncologists need to make sure that people qualify for the medication. This includes:

• Stage 4 disease: Documenting that a person has metastatic breast cancer (stage 4) is needed, meaning that the breast cancer has spread beyond the breast and nearby lymph nodes to the bones, liver, lungs, brain, distant lymph nodes, skin, the chest wall, or other distant regions. Roughly 5% to 6% of people with breast cancer have metastatic disease at the time of diagnosis, but for 94% to 95%t of people, metastatic disease represents a distant recurrence of previous early-stage breast cancer.
• Receptor status: The tumor must be estrogen receptor-positive and HER2 negative. It's important to note that receptor status can change with progression or metastasis of breast cancer (tumors that are estrogen receptor-positive when early stage may become estrogen receptor-negative when metastatic, and vice versa. The same applies to HER2.) A repeat biopsy of a site of metastasis is usually recommended.
• Previous endocrine therapy with progression: Oncologists must document that hormonal therapy such as an aromatase inhibitor has been used and that progression occurred while on or after use of the drug.
• A positive test for the PIK3CA mutation

Testing for PIK3CA Gene Mutations

Testing for a PIK3CA mutation should be done via the corresponding approved test called the Therascreen PIK3CA RGQ PCR Kit. The kit can detect 11 different mutations on the PIK3CA gene, including the three "hotspot" codons (H1047R, E545K, and E542K) that are found in roughly 80% of people with metastatic breast cancer.

Mutation testing may be done using a tissue sample (biopsy specimen) or blood test for cell-free DNA (liquid biopsy). If a liquid biopsy is negative for the mutation, a follow-up tissue biopsy is recommended to confirm the absence of the mutation.

The approval of Piqray emphasizes the importance of genetic testing in advanced breast cancer.

Precautions and Contraindications

Piqray should not be used by women who are pregnant or may become pregnant, and effective birth control should be used during treatment and for at least one week after discontinuation of the drug. In animal studies, the medication was associated with miscarriage, low birth weight, and birth defects.

The effect of Piqray on breastfeeding is unknown, and women should not breastfeed while using the medication and for at least one week after the drug is discontinued.

Men being treated with Piqray who have a partner of reproductive age should use effective contraception during use and for one week after discontinuation of the drug.

The drug is also contraindicated in people who have had a severe hypersensitivity reaction to Piqray or one of its components.

Piqray should not be used by people who have a history of severe skin reactions such as Stevens-Johnson syndrome, erythema multiforme, or toxic epidermal necrolysis.

Since the medication commonly causes increased blood sugar levels (hyperglycemia), special caution should be taken in people who have Type 1 diabetes or Type 2 diabetes. This includes testing fasting blood glucose, HgA1C, and optimizing blood sugar control before starting the drug.

Dosage

According to the manufacturer, Piqray is available in 50 milligram (mg), 150 mg, and 200 mg tablets.

The usual starting dosage of Piqray is 300 mg (two 150 mg tablets) orally one time daily, taken at the same time each day.

Piqray is used along with Faslodex (fulvestrant) 500 mg in an intramuscular injection (IM) on days 1, 15, and 29 of the first month, and then monthly thereafter.

If a reduced dosage is needed, lower dose tablets should be used as Piqray should not be split. If tablets appear damaged or broken they should not be used.

Modifications

The dose of Piqray does not need to be modified for:

• People of older age, though patients 65 and younger experienced a higher incidence of grades 3 and 4 hyperglycemia
• People with mild to moderate kidney disease
• People with hepatic impairment at baseline before staring the drug.

Dose modification may be needed for certain adverse reactions including hyperglycemia, diarrhea, and rash, and is done as a two-step reduction:

• First dose reduction: The dose is reduced from 300 mg to 250 mg daily
• Second dose reduction: The dose is reduced to 200 mg daily

No dose reduction is permitted beyond 200 mg/day, and only one dose reduction is permitted for pancreatitis.

How to Take and Store

Piqray should be taken with food at the same time each day. When taken on an empty stomach, it appears that less of the drug is absorbed to enter the bloodstream.

If a dose is missed, it may be taken the same day if it is within nine hours of the time usually taken. If more than nine hours have passed, the medication should be skipped until the next day.

If you vomit after taking Piqray, you should not take another dose but instead wait until the next day to take the medication.

Piqray should be stored at room temperature between 68 and 77 degrees Fahrenheit (20 to 25 degrees Celsius).

Side Effects

Side effects are common on Piqray, but many of these can be managed conservatively, with medications, or by changing the dose when needed.

Common

The most common side effects while taking Piqray plus Faslodex include:

• Elevated blood sugar
• Rash
• Diarrhea
• Nausea
• Decreased appetite
• Weight loss
• Mouth sores
• Hair loss
• Fatigue

Severe

The most common severe (grade three or grade four) adverse reactions in clinical trials were hyperglycemia (36.6% on Piqray versus 0.7% on Faslodex alone), rash (25% versus 4.2%), and diarrhea (6.7% versus 0.3%).

When serious side effects occur, a first or second dose reduction may be needed or the drug may need to be discontinued altogether.

Hypersensitivity: Severe allergic reactions may occur and require immediate medical care. Symptoms of a severe allergic reaction (anaphylaxis) may include difficulty breathing, swelling of your lips, mouth, or throat, rash or flushing of the skin, rapid heart rate, weakness, and eventually unconsciousness if not treated. People who have had evidence of a severe hypersensitivity reaction on Piqray should permanently discontinue the medication.

Severe skin reactions: Symptoms may include a severe skin rash, skin redness (like a sunburn), blistering of the skin or mucous membranes around the mouth, lips, and eyes, or skin peeling (like after a bad sunburn). Fever and flu-like symptoms may also occur. If a severe skin rash (such as Stevens-Johnson syndrome) develops, Piqray should be stopped until it known whether or not the drug is the cause. If Piqray is determined to the be the cause the medication must be discontinued.

Hyperglycemia: An increase in blood sugar, sometimes seriously high, was common in clinical trials with Piqray. Symptoms of hyperglycemia may include increased thirst, increased urination, weight loss despite an increased appetite, and dry mouth. Depending on the level of blood glucose, treatment may include monitoring, stopping the drug for a time, using a reduced dose of the drug, or discontinuing the drug. Guidelines are available to healthcare providers on the recommended changes to be made based on blood glucose values.

Pneumonitis: Pneumonitis, or inflammation of lungs may occur while taking Piqray. Symptoms may include shortness of breath, a cough, or chest pain. If a diagnosis of pneumonitis is confirmed (which can be challenging in the setting of advanced cancer), Piqray should be discontinued.

Diarrhea: Diarrhea may occur and should be reported to your healthcare provider. Severe or persistent diarrhea can lead to dehydration. Dehydration, in turn, can lead to kidney damage if not treated. Initial treatment may include increasing oral fluids and anti-diarrheal medications.

Other serious side effects: Other serious adverse reactions that occurred in 2% or more of people included acute kidney injury, abdominal pain, and anemia. Osteonecrosis of the jaw was also noted in 4.2% of people, but all of these people were being treated or had previously been treated with bone modifying drugs (drugs associated with osteonecrosis of the jaw).

Warnings and Interactions

Piqray may interact with some common medications, resulting in either an increased or decreased dose of the drug. It's important to tell your healthcare provider about any medications, over-the-counter drugs, or nutritional supplements you are taking.

Examples of mechanisms and drugs that may increase or decrease the activity of Piqray include:

CYP3A4 Inducers: Drugs that are considered CYP3A4 inducers can decrease the concentration (and activity) of Piqray. Some of the drugs that are CYP3A4 inducers include:

• Phenobarbital
• Phenytoin
• Rifampin
• Glucocorticoids
• Modafinil
• Carbamazepine
• St. John's wort

CYP2CP Substrates: Piqray may decrease the concentration of drugs that are considered CYP2CP substrates. Examples include:

• Ibuprofen, including Motrin and Advil
• Sulfamethoxazole (a component of the antibiotic Septra and Bactrim)
• Metronidazole
• Coumadin (warfarin)
• Glucotrol (glipizide) for diabetes
• Celebrex (celecoxib)
• Amiodarone

BRCP Inhibitors: Drugs in this category may increase the serum levels of Piqray resulting in greater side effects or toxicity. Drugs in this category include:

• Some chemotherapy drugs
• Tagamet (cimetidine)
• Sulfasalazine
• Glyburide
• Minipress (prazosin)

It's important to note that the drugs noted are only a few of the more commonly used drugs that can interact with Piqray, and your oncologist and pharmacist should be aware of all medications you are taking.

A Word From Verywell

The approval of Piqray provides yet another treatment option for people coping with metastatic breast cancer, and can improve progression-free survival for some people.

Reading about the potential side effects, however, can sometimes be daunting. It's important to look at the big picture when considering side effects that you are willing to tolerate, especially in the setting of metastatic cancer.

Rather than looking at side effects alone, these need to be compared to the "side effects" of your cancer progressing without treatment. Even when treatments do not extend life, they may improve your quality of life by slowing the growth of cancer, and the symptoms related to that growth.