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Men with metastatic hormone-resistant prostate cancer (mCRPC) given Lynparza® (olaparib), a breast and ovarian cancer treatment, lived a clinically meaningful longer time without disease progression or death compared to those given standard treatment with Xtandi® (enzalutamide) or Zytiga® (abiraterone) in a Phase 3 trial. These eligible patients had a mutation in one of 15 DNA repair genes involved in the homologous recombination (HR) pathway. Specifically, these positive benefits were seen in patients with mutations in BRCA1, BRCA2, or ATM, the most common among HR gene mutations; the first two are also strongly linked with familial breast and ovarian cancers. Overall, HR mutations occur in approximately 25% of men diagnosed with mCRPC.

The multicenter, open-label PROfound study (NCT02987543) compared the efficacy and safety of Lynparza® to that of Xtandi® (from Astellas and Pfizer Oncology) and Zytiga® (from Janssen) in mCRPC patients whose disease had progressed while on these newer hormone treatments.

Lynparza®, an oral PARP (poly ADP-ribose polymerase) enzyme inhibitor marketed by AstraZeneca and Merck, is intended to prevent cancer cells from repairing their DNA errors, thereby causing their death. It is approved for some breast and ovarian cancers.

Patients in PROfound were treated with 300 mg twice daily of Lynparza®, or investigators’ choice of Xtandi® (160 mg daily) or Zytiga® (1,000 mg daily, plus prednisone). Lynparza’s safety and tolerability results were generally consistent with previous trials. The PROfound trial is expected to fully conclude in February 2021.

“This is the only positive Phase 3 trial of any PARP inhibitor in metastatic hormone-resistant prostate cancer, where the need for new, effective therapies is high,” according to José Baselga, AstraZeneca’s executive vice president, Oncology R&D. “The PROfound trial also demonstrates the potential value of genomic testing in this at-risk patient population.”  Roy Baynes, senior vice president, head of global clinical development and chief medical officer at Merck Research Laboratories, said trial results “represent the potential for a new, oral, and targeted treatment option for this patient population.”

Lynparza® is being tested in other prostate cancer trials, including the international PROpel Phase 3 study testing the addition of Lynparza® to Zytiga® as a first-line treatment of mCRPC patients who have not been given chemotherapy or newer hormonal agents (NCT03732820). PROpel is currently enrolling up to 720 men at sites across the U.S., Canada, Europe and elsewhere.

The material above was summarized from an article appearing in Prostate Cancer News Today, August 12, 2019 to which an e mail subscription is highly recommended.

Additional note on how PARP inhibitors work. DNA is damaged thousands of times during each cell multiplication cycle, and that damage must be repaired, including in normal as well as in cancer cells (which multiply and grow faster than normal cells). Otherwise, if DNA damage is not repaired, cells may die due to this damage. BRCA1, BRCA2 and PALB2 are proteins in cells that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway. PARP1 is a protein that is important for repairing single-strand breaks (‘nicks’ in the DNA). Drugs that inhibit PARP1 cause multiple double strand DNA breaks to form in this way, and in tumors with BRCA1, BRCA2 or PALB2  mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don’t replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair system operating, which allows them to survive the inhibition of PARP by drugs like Lynparza®.

The treatment landscape for metastatic prostate cancer is shifting and expanding yet again, according to new findings from two large clinical trials presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO). The ENZAMET trial tested the drug enzalutamide (Xtandi) and the TITAN trial tested apalutamide (Erleada) in men whose cancer is still responsive to hormone-suppressing therapies—also called castration-sensitive prostate cancer. In both trials, combining the respective drugs with the androgen deprivation therapy (ADT) substantially improved how long men lived overall and how long they lived without their cancer getting worse.

The ENZAMET trial enrolled more than 1,100 men with hormone-sensitive metastatic prostate cancer. The men were randomly assigned to ADT combined with enzalutamide or with any of three other androgen-blocking drugs. At a median follow-up of nearly 3 years, men who received ADT plus enzaluatamide had a 33% reduced risk of death, with 80% still alive compared with 72% of men treated with ADT plus another antiandrogen drug. Men in the enzalutamide group also had better clinical progression-free survival (PFS), which the research team defined as the time until the return of disease-related symptoms, the detection of new metastases on imaging scans or the initiation of another cancer treatment for prostate cancer, whichever came first. At 3 years, 63% of men in the enzalutamide group were alive without clinical progression of their disease, compared with 33% in the standard treatment group. Although enzalutamide appeared to be effective regardless of whether men had high- or low-volume disease, one apparent differentiating factor was planned early treatment with docetaxel (taxotere). Nearly half of the men in both treatment groups received early treatment with docetaxel and, for those men, enzalutamide was not associated with longer overall survival.

From the standpoint of efficacy, similar results were seen in the TITAN trial with apalutamide (Erleada). Funded by the drug’s manufacturer, Janssen Pharmaceuticals, the trial enrolled more than 1,000 men with hormone-sensitive, metastatic prostate cancer, with participants randomly assigned to receive ADT along with a placebo or ADT plus apalutamide. At 2 years of follow-up, approximately 82% of men who received ADT plus apalutamide were still alive compared with 74% in men treated with ADT plus placebo, for a 33% reduction in the risk of death. The trial’s other primary measure was the amount time men lived without evidence on imaging scans that their disease had progressed, known as radiographic PFS. At a median follow-up of nearly 2 years, men treated with ADT plus apalutamide had a 50% improvement in radiographic PFS than men treated with ADT alone.

What factors would influence the choice of treatments? In the case of enzalutamide and apalutamide, Dr. William Dahut, clinical director of the National Cancer Institute’s Center for Cancer Research said, both drugs “may be particularly good choices for men with low-volume disease, who might shy away from docetaxel” due to concerns about side effects. Unlike docetaxel, which must be administered intravenously in the hospital, enzalutamide, apalutamide, and abiraterone are oral drugs that can be taken at home, so they also offer greater convenience for patients. On the other hand, many patients tolerate docetaxel quite well, Dr. Dahut noted, and it’s given for a fixed duration, not continuously like the other drugs. Other factors such as insurance costs may also affect treatment choice.

For additional details, see the following article published June 19th, 2019 on line by the National Cancer Institute (NCI) Cancer Currents Blog.

A recent study presented on May 3-6 at the American Urological Association’s 2019 Meeting found that treating metastatic, hormone-resistant prostate cancer (mCRPC) patients (who had not received chemotherapy) with Xtandi (enzalutamide) leads to better survival outcomes and lower healthcare costs than Zytiga (abiraterone acetate).

While therapies that lower male sex hormones (testosterone) — required for prostate cancer to survive and grow — are a mainstay of therapy for advanced prostate cancer, most patients will eventually acquire resistance to such approaches. This often happens because the cellular receptor for these hormones, called the androgen receptor, becomes constantly active, even in the absence of androgens. Therapies that inhibit the androgen receptor — such as Pfizer and Astellas’ and Xtandi and Janssen’s Zytiga — have largely improved the overall survival of prostate cancer patients, and are now approved for mCRPC patients in the U.S. and Europe. However, which treatment brings the most benefits or the lowest healthcare costs has not been addressed.

In this study, researchers performed a retrospective study to compare the overall survival and healthcare costs associated with these two second-generation androgen receptor inhibitors. They examined data from 3,174 adult men with mCRPC who had not received chemotherapy for at least one year before starting treatment with either Xtandi or Zytiga. Patients had been treated between April 2014 and March 2017, and their data were recovered from the Veterans Health Administration (VHA) database. Overall, 1,945 patients, mean age 73, received Zytiga, while Xtandi was administered to the remaining 1,229 patients, mean age 74.

After examining outcomes of these patients, researchers found that those on Xtandi lived for a median of 30 months, compared to 26 months for Zytiga. This represented a significant 17% reduction in mortality risk with Xtandi. Xtandi-treated patients also required fewer outpatient visits — both overall and cancer-related — than those treated with Zytiga, indicating that Xtandi led to a reduced use of medical resources. In line with this, Xtandi patients had fewer healthcare costs than Zytiga patients. In total, a patient treated with Xtandi would have a monthly healthcare cost of $8,085, compared to $9,092 for Zytiga. Prostate cancer-related costs were also lower for Xtandi — $6,321 versus $7,280.

Thus, researchers concluded that “chemotherapy-naive mCRPC patients treated with Xtandi had better survival, significantly lower resource use and healthcare costs than patients treated with Zytiga.”

The above appeared in the e mail Prostate Cancer News Today, May 16th, 2019.