Early Aggressive Treatment Urged for Metastatic Prostate Cancer

Pam Harrison

May 01, 2019

Early initiation of life-prolonging treatment for men with high-risk metastatic castration-sensitive prostate cancer (mCSPC) appears to be critical. This is the main lesson from the final analysis of the LATITUDE study, which clearly shows the value of managing rapidly progressive disease aggressively, suggests editorialist Fred Saad, MD, University of Montreal, Quebec, Canada.

The LATITUDE trial showed the impact of adding abiraterone acetate (Zytiga, DCS Pharma) plus prednisone to standard androgen deprivation therapy (ADT) for men with newly diagnosed mCSPC.

It significantly improved overall survival (OS) to a median of 53.3 months compared to only 36.5 months with ADT alone (P < .0001).

These are the final study results, reported by Karim Fizazi, MD, University of Paris Sud, Villejuif, France, and colleagues. They were published online April 12 in the Lancet Oncology.

These results "support the use of abiraterone acetate plus prednisone as a standard of care in patients with high-risk mCSPC," the authors conclude.

In an accompanying editorial, Saad takes that conclusion a step further, stating that if a patient who is diagnosed with either mCSPC or metastatic castration-resistant prostate cancer (mCRPC) does not receive at least one additional life-prolonging therapy such as abiraterone in addition to ADT, "that should now be considered suboptimal care," he writes.

However, in the real-world setting, treatment of high-risk disease is more often than not delayed, Saad commented to Medscape Medical News.

"It's human nature to wait until patients become symptomatic, until they progress, or because you don't want to increase the cost or side effects from treatment, so for all sorts of reasons in the real-world setting, treatment is delayed, and then you end up having dismal survival in these patients," Saad commented in an interview.

He emphasized that "if you don't start up front early, you end up starting too late."

If you don't start up front early, you end up starting too late. Dr Fred Saad

As the control arm in LATITUDE clearly demonstrated, "patients who didn't get up-front treatment progressed quite quickly," he added.

Therefore, either abiraterone or docetaxel should always be considered in addition to ADT in patients with high-risk prostate cancer, such as the ones included in LATITUDE, Saad noted.

This advice follows the recommendation in the latest clinical practice guidelines for the treatment of metastatic noncastrate prostate cancer from the American Society of Clinical Oncology, which describe treatment with either abiraterone or docetaxel as standard of care.

Poorer Outcomes on ADT Alone

Saad told Medscape Medical News that his reasoning is supported by the details of the LATITUDE study.

"Looking at the results, I was struck by several important findings," he writes.

First, the median OS in men who initially received placebo plus ADT in LATITUDE was only about 3 years, he points out. This OS rate is "strikingly" similar to that seen in men with mCRPC treated with either abiraterone or enzalutamide (Xtandi, Astellas Pharma) in the phase 3 registration trials.

This means that patients who were treated with ADT alone survived only 3 years from the time of diagnosis, although, Saad points out, they could have been treated with life-prolonging therapies when they transitioned to the state of castration resistance.

"Looking closely at the data, we realise that the patients in LATITUDE actually became castration resistant in only 7 months on ADT alone," Saad emphasizes.

Because subsequent therapy was only initiated some 14 months later, these patients ended up dying less than a year after that.

"Clearly, patients with high-risk metastatic prostate cancer are likely to progress quickly and die from, rather than with, prostate cancer," Saad observes.

This fact necessitates the immediate introduction of life-prolonging therapies, including treatment with abiraterone and docetaxel in the setting of high-risk metastatic disease, because early use maximizes the desired therapeutic benefit before castration resistance develops, he argues.

Once castration resistance develops, it is very unlikely that these therapies will be as effective, he adds.

This was proven by data from LATITUDE, in which almost half of patients who were slated to receive abiraterone after ADT died of the disease and never received the drug at all, he maintains.

Furthermore, median progression-free survival — a secondary endpoint in LATITUDE — was only 30.1 months in the group that initially received placebo, compared to 53.3 months for the group that received abiraterone plus prednisone.

"[This finding] suggests that patients who did receive subsequent therapy at a median time to subsequent therapy of 21.2 months...did not respond for very long, given the short time (about 9 months) between these events," Saad elaborates.

Abiraterone or Decetaxel?

In an interview about the new ASCO guidelines, lead author Michael J. Morris, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News that in choosing between docetaxel and abiraterone, many factors should be considered.

He said that "on the practical side, six doses of chemotherapy takes about 18 weeks to achieve," whereas abiraterone is taken continuously.

Patients who want to finish their treatment quickly may prefer docetaxel, said Morris.

The second consideration is financial and relates to the healthcare system under which the patient receives care.

He explained: "For patients who don't have drug coverage, the chemotherapy option could be quite a bit cheaper than the abiraterone option."

As previously reported by Medscape Medical News, 10 cycles of generic docetaxel plus ancillary costs amount to $14,839, whereas 6 months of abiraterone plus prednisolone costs $30,000.

Morris continued: "From a scientific standpoint, we don't actually know which is better, but there are some patients who have disease which may not be entirely driven by the androgen receptor; that is, patients may have quite a bit of metastatic disease, in which case chemotherapy might be the more biologically appropriate option."

He added: "We don't know that for certain, but for patients who either have very high-grade disease, are poor prostate-specific antigen producers, have a neuroendocrine component or a small cell component, they may do better with chemotherapy than with abiraterone."

Another consideration is toxicity. Morris said that the "major force that is in favor of abiraterone is that it's really well tolerated. It's easy to take."

He summarized: "There are practical concerns, quality-of-life concerns, financial concerns, and biological concerns why a doctor and a patient might put their heads together and decide on one option vs another."

Saad points out that there may be situations in which docetaxel is the only option, such as in countries where abiraterone is not available, is too expensive, or is not an option even if approved for hormone-sensitive prostate cancer.

In these situations, Saad suggests that patients be closely monitored for a suboptimal treatment response after 6 to 8 months of therapy. A suboptimal response is reflected by a prostate-specific antigen nadir >0.2 ng/mL, he states.

"Since these patients will probably have earlier progression and mortality, immediate therapy could be considered or patients should at least by monitored closely," Saad writes.

However, in countries where abiraterone is an option, "it's become almost unethical to do only ADT unless there is a really compelling reason why you can't do something more," he emphasized.

Saad also emphasized that once patients develop mCRPC, early introduction of an approved mCRPC drug, including both abiraterone and enzalutamide, is also warranted.

Saad received grants and personal fees from Janssen, Astellas, and Sanofi during the conduct of the study, as well as grants and personal fees from Bayer for outside research.

Lancet Oncol. Published online April 12, 2019. Abstract, Editorial

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