- A multinational, phase 3 clinical trial – TALAPRO-2 – tested whether the combination of two medicines, talazoparib and enzalutamide, may improve clinical outcomes in adult men with metastatic castration-resistant prostate cancer.
- Treatment with talazoparib and enzalutamide resulted in a 37% reduced risk of cancer progression or death, compared to treatment with placebo and enzalutamide.
- The Food and Drug Administration (FDA)’s decision on whether or not this combination therapy may be used to treat men with metastatic castration-resistant prostate cancer is expected in 2023.
Androgens (male hormones) such as testosterone help prostate cancer cells grow. Sometimes, prostate cancer continues to grow even when testosterone levels in the blood are suppressed. This is known as
If the cancer spreads from the prostate gland to other parts of the body, such as the lymph nodes and bones, it is classified as metastatic castration-resistant prostate cancer.
In recent years, there have been great improvements in the treatment of metastatic castration-resistant prostate cancer. Despite this progress, currently available treatments have a short-duration effect, and the cancer can start growing again after treatment.
They tested the efficacy and safety of this combination therapy in a phase 3 trial, TALAPRO-2.
The results of the clinical trial were presented at the 2023 ASCO Genitourinary Cancers Symposium by Dr. Neeraj Agarwal, professor of oncology and Presidential Endowed Chair of Cancer Research at Huntsman Cancer Institute, University of Utah, and lead investigator for TALAPRO-2.
Enzalutamide is a type of hormone therapy that is approved to treat men with prostate cancer. It works by blocking testosterone, without which the prostate cancer cells cannot grow, even if they have spread to other parts of the body.
Talazoparib belongs to a class of cancer drugs known as poly-ADP ribose polymerase (PARP) inhibitors. PARP is an enzyme (protein) found in cells, which helps damaged cells repair themselves. PARP inhibitors are used in cancer treatment to block the repair function of PARP in cancer cells, causing the cells to die.
This led researchers at Pfizer to develop a combination therapy consisting of the PARP inhibitor talazoparib and the testosterone-blocking enzalutamide.
The study began in December 2017 and enrolled adult men with metastatic castration-resistant prostate cancer from 26 countries.
The participants were randomized to receive either:
- talazoparib 0.5 milligrams (mg) and enzalutamide 160 mg once daily — this applied to 402 participants
- or a placebo and enzalutamide 160 mg once daily — this applied to 403 participants.
The primary aim of the TALAPRO-2 trial was to find out if combining talazoparib with enzalutamide increases radiographic progression-free survival (rPFS), the length of time patients live without their cancer getting worse, compared to placebo plus enzalutamide.
The researchers also tested the DNA from the cancer cells of all study participants to check if they had faulty DNA repair genes.
The median follow-up time was similar for both treatment groups: 24.9 months for the combination therapy group and 24.6 months for the placebo plus enzalutamide group.
The results showed that talazoparib plus enzalutamide reduced the risk of disease progression or death by 37% versus placebo and enzalutamide. This was regardless of the presence or absence of DNA repair gene mutations, known as “
“TALAPRO-2 is the second randomized phase 3 trial to demonstrate a benefit with combination [androgen receptor] plus PARP inhibition in delaying rPFS in the first line [metastatic castration-resistant prostate cancer] setting, joining [the] PROPEL [study],” said Dr. Andrew J. Armstrong, professor of medicine, surgery, pharmacology and cancer biology, and director of research at the Duke Cancer Institute Center for Prostate and Urologic Cancers, not involved in the current study.
“The delays in rPFS are clinically meaningful, ranging from over 50% relative improvements in HRR+ patients to 30-40% improvements in HRR-undetected patients,” Dr. Armstrong explained.
Dr. Cora N. Sternberg, an oncologist at Weill Cornell Medicine specializing in genitourinary cancer, and professor of medicine at the Englander Institute for Precision Medicine, not involved in the research, also drew parallels between TALAPRO-2 and the PROPEL study.
She added that the results of TALAPRO-2 “differ from what was seen in the MAGNITUDE study with niraparib and abiraterone, where those without HRR deficiency (biomarker negative) group were stopped early due to lack of efficacy.”
At the time the trial results were presented, data on overall survival were “immature,” meaning that more time is needed to determine if combination therapy with talazoparib and enzalutamide helps patients to live longer compared to placebo and enzalutamide.
Dr. Nicholas Zorko, assistant professor of medicine at the Masonic Cancer Center, University of Minnesota, not involved in the study, told Medical News Today that there is “a spirited debate in the field [as to] whether rPFS is sufficient, or if there must also be a significant overall survival benefit to truly say that there is a therapeutic benefit.”
The study also measured any side effects men had while taking the combination therapy.
The most common side effects were:
- anemia (65.8%)
- decreased neutrophil count (35.7%)
- fatigue (33.7%)
- decreased platelet count (24.6%)
- decreased leukocyte count (22.1%)
- back pain (22.1%)
- decreased appetite (21.6%)
- nausea (20.6%).
“Given what we know about the side effects of PARP inhibitors, the significant anemia and neutropenia in the combination therapy group is not surprising,” Dr. Zorko told MNT.
He also cautioned that “the need for transfusions and dose-discontinuation should be taken into consideration before starting combination therapy, especially since 49% of patients had anemia prior to therapy.”
“Additionally, the time toxicity needed to receive transfusions and supportive care in the clinic may reduce the enthusiasm of patients for this oral combination regimen,” he noted.
Dr. Armstrong commented that “there is more toxicity and costs to patients [receiving] combination [therapy]; […] however, these are manageable for most patients and do not seem to impair quality of life long-term in most patients with [dose] adjustments and side effect management.”
In comments to MNT, Dr. Scott T. Tagawa, professor of medicine and urology at Weill Cornell Medicine, not involved in the current study, identified the “early data for overall survival as well as [unknown] long-term adverse events” as the key limitations of this study.
Dr. Zorko further noted: “In the study, only 5.2% of patients had been previously treated with abiraterone. As [triple therapy with] androgen-deprivation therapy, docetaxel, abiraterone/ prednisone is becoming more widely utilized in the metastatic [hormone-sensitive prostate cancer] setting, we will see more patients in this space as they become castration-resistant, but whether this particular subgroup benefits will be intriguing to see.”
The phase 3 clinical trial was the final phase of drug development. Now, the FDA must review the clinical trial data and decide whether or not this treatment can be used in patients with metastatic castration-resistant prostate cancer. The FDA’s decision regarding the clinical application is expected in 2023.
Dr. Armstrong told MNT:
“[T]here is still much work to be done to understand which patients have the greatest rPFS and survival benefits with combination therapy, and conversely which patients experience no benefits or even harms from this approach. This may come from larger studies, registries, combination meta-analyses across trials, and careful analysis of both clinical and broad genomic analyses.”
Another aspect that requires further investigation is the mechanism of action whereby PARP inhibitors work in synergy with testosterone-blocking drugs like enzalutamide. According to Dr. Sternberg, this “has not been clearly determined and […] has become a highly controversial topic.”