New drug combination stops prostate cancer growth in phase 3 clinical trial

An international study reports that the combination of two drugs could significantly retard the development of a dangerous form of prostate cancer in men who have specific mutations in DNA repair genes.

The large Phase 3 AMPLITUDE trial, led by University College London's Cancer Institute professor Gerhardt Attard had established whether adding niraparib to the standard combination of abiraterone acetate and prednisone helped men whose cancer had spread but was still hormone-sensitive.

Prostate cancer is more likely to arise in response to hormones found in men, and initial therapy works to reduce levels of androgens. But when the disease is also found with mutations in DNA repair genes—chiefly BRCA1 and BRCA2—the illness can spread faster and become increasingly resistant to treatment.

These genetic changes are seen in about one of every four men with late-stage prostate cancer. Researchers asked whether starting a PARP inhibitor like niraparib earlier in treatment would prevent the development of cancer for longer than with standard therapy alone.

The AMPLITUDE trial recruited 696 men with 32 nations who had newly diagnosed metastatic, hormone-sensitive prostate cancer and at least one HRR gene mutation. Median age was 68 in participants, who were randomly assigned to receive niraparib with abiraterone and prednisone or a placebo together with the same usual care. The doctors and patients did not know which treatment each patient was receiving.

More than half of those enrolled had BRCA1 or BRCA2 gene mutations, while most had extensive cancer spread at diagnosis. The study followed patients for about two and a half years, tracking whether the cancer worsened, how long they remained symptom-free, and how long they lived.

The results were striking. In all patients, niraparib reduced the risk of cancer progression by 37 percent compared to standard treatment alone. In men with a mutation in the BRCA1 or BRCA2 genes, the risk was reduced by nearly half—approximately 48 percent.

At the conclusion of the period of study, cancer progression had not yet reached a median point within the niraparib arm, and most patients were thus still without fresh proof of disease, compared to an average of just over two years in the control arm.

The time until symptoms worsened also doubled in those receiving niraparib. Only 16 percent of the patients receiving niraparib had significant worsening of symptoms, compared with 34 percent in the placebo group. While researchers detected a trend toward improved survival overall, the data are too early to determine any definite improvement in life expectancy.

These findings are striking because they make widespread genomic testing at the time of diagnosis followed by use of a personalized treatment in those who will be most benefited feasible," Professor Attard said. "By combining niraparib with standard therapy, we can delay the time the cancer comes back and, hopefully, significantly extend life expectancy."

As with nearly all cancer medications, side effects happened more frequently with the combination therapy. Anemia and high blood pressure were the most common issues among men treated with niraparib. Almost 30 percent came down with anemia that required blood transfusions, versus less than 5 percent in those on therapy alone.

Roughly one-quarter of patients treated with niraparib required at least one transfusion, though the majority continued treatment after dose modification or with supportive therapy.

More severe side effects—those scored at level 3 or 4—were experienced by roughly 75 percent of the niraparib cohort, as compared with 59 percent in the control group. Side effect discontinuation was still relatively minimal: roughly 15 percent for niraparib as compared with 10 percent for placebo. Fourteen patients who received niraparib died because of treatment-related events, such as infection, heart disorder, and multiorgan failure, as compared with seven in the control group.

Though these figures sound ominous, researchers stressed that most reactions were temporary and manageable. "For tumors with a mutation in one of the eligible HRR genes, a doctor should consider talking to a patient about a trade-off of side-effect risk versus a certain benefit to slowing disease progression and worsening symptoms," Attard said.

The AMPLITUDE trial is a milestone: it is the first significant evidence that a PARP inhibitor like niraparib can help in hormone-sensitive prostate cancers, not only in advanced, resistant ones. The drug does this by blocking an enzyme called PARP used to repair damage to cancer cells' DNA. Without that, cancer cells cannot survive. In addition to hormone-suppressing drugs such as abiraterone, niraparib also appears to keep the cancer from discovering an alternate route for expansion.

However, the advantage was greatest in patients with BRCA1 or BRCA2 mutations. In patients with defects in other HRR genes, such as CHEK2 or FANCA, results were unknown. The trial was meant to test broader HRR groups rather than single mutations, and therefore scientists caution that all patients with a defect in DNA repair may not realize the same benefit.

In spite of this, the results support an emerging consensus among oncologists that genetic testing can become standard for men with recently diagnosed advanced prostate cancer. Early detection of mutations in genes could help doctors pair patients with more effective, less toxic therapies right from the beginning.

Globally, prostate cancer affects about 1.5 million men each year, and it is one of the most common cancers in men. More than 56,000 men are diagnosed every year in the United Kingdom alone, and about 12,000 men die of prostate cancer. In most cases, regular hormone therapy controls cancer for a few years. However, in others with aggressive gene alterations, the disease recurs earlier and progresses more rapidly.

Niraparib is already licensed in the U.K. to treat certain ovarian cancers but not to treat prostate cancer. The National Institute for Health and Care Excellence said it will postpone making a decision until it has more survival data. But researchers hope the findings will lead to more patients having their genomes tested and faster access to treatment.

In the meantime, doctors warn men not to be too hasty to change treatments without consulting their oncologists. The most significant implication of the trial, the authors say, is the potential—but also the need for monitoring and individualized treatment.

Given supportive extended follow-up, this dual therapy could become a new standard of care for men with HRR mutation prostate cancer. For patients with a BRCA1 or BRCA2 mutation, beginning niraparib early can gain decades of time before the disease has progressed.

Outside of prostate cancer, the study strengthens the case for using genetic testing to guide the treatment of additional cancers—matching treatments with the genetics of each tumor.

For scientists, the findings could open the door to additional trials of PARP inhibitors across other hormone-sensitive forms of cancer.

Research findings are available online in the journal Nature Medicine.

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