Adding Nubeqa to Therapy May Reduce PSA Levels in Metastatic Hormone-Sensitive Prostate Cancer

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Men with metastatic hormone-sensitive prostate cancer treated with Nubeqa, androgen-deprivation therapy and docetaxel had reductions in PSA levels that were associated with improved overall survival and a prolonged time to PSA progression.

Men with metastatic hormone-sensitive prostate cancer treated with Nubeqa (darolutamide) plus androgen-deprivation therapy and docetaxel experienced rapid and durable reductions in prostate-specific antigen (PSA) levels, according to a recent study analysis.

Findings from the analysis of the ARASEN trial presented at the 2023 AUA Annual Meeting demonstrated that these PSA reductions were linked to improved overall survival (the time from treatment that a patient with cancer is still alive) and a prolonged time to PSA progression compared with androgen-deprivation therapy plus docetaxel alone.

“Giving docetaxel, (androgen-deprivation therapy) and (Nubeqa), we've got much better PSA responses,” Dr. Fred Saad, chief of urology and director of GU oncology at the University of Montreal Hospital Centers, said in an interview with our sister publication, Urology Times, at the AUA meeting. “What's most important is that we got much better undetectable PSA responses, which is now our new objective as an early signal that we're doing the right thing and going in the right direction.”

PSA Response

At study entry, median PSA levels were 30.3 ng/mL for patients assigned Nubeqa and 24.2 ng/mL for those assigned a placebo. According to the National Cancer Institute, PSA levels of 4.0 ng/mL and lower are considered normal, although some patients with low PSA levels may also develop prostate cancer.

The Nubeqa group, compared with the placebo group, demonstrated rapid PSA reductions of at least 50% and at least 90% at weeks 12, 24, 36, 52 and at any time throughout the study. Further, the addition of Nubeqa significantly prolonged time to PSA progression, compared with the control arm.

When evaluating the association between achievement of undetectable PSA (levels of less than 0.1 ng/mL) at 24 and 36 weeks and time to PSA progression among patients treated with Nubeqa, risk was reduced by 72% and 77%, respectively, compared with patients who did not achieve undetectable PSA.

Investigators also found that the addition of Nubeqa was associated with deep PSA responses compared with placebo.

Amongst the deep responses, undetectable PSA was achieved in more than twice the number of patients receiving Nubeqa versus those receiving a placebo at 24 weeks (48.7% versus 23.9%, respectively), which continued to increase at 36 weeks (57.1% versus 25.1%), 52 weeks (60.2% versus 26.1%), and at any time (67.3% versus 28.6%).

Lastly, and most importantly to Saad, patients who were treated with Nubeqa demonstrated an association between achievement of undetectable PSA at 24 and 36 weeks with improved overall survival, reducing the risk for death by 53% and 63%, respectively, compared with patients who did not achieve undetectable PSA. In particular, the median undetectable PSA at 36 weeks was unable to be estimated and 33.3 months, respectively, reducing the risk for death by 63%.

“This is going to be our new challenge: What do we do in these patients that don't get better within 6 months?” Saad added. “This is our new strategy for clinical trials. Should we further intensify? They're already getting a triplet, what can we add? What is making it that they are not getting to undetectable?”

ARASENS Trial Background

In the ARASENS trial, investigators randomized 1,306 patients with metastatic hormone-sensitive prostate cancer to receive either Nubeqa or matching placebo in combination with androgen-deprivation therapy and docetaxel.

Overall survival served as the primary focus of the study.

As of the data cut-off date of October 25, 2021, the addition of Nubeqa significantly reduced the risk for death by 32.5% compared with androgen-deprivation therapy plus docetaxel. Further, the incidence of treatment-emergent side effects was similar between the Nubeqa group and the placebo group.

Investigators measured serum PSA at screening, and every 12 weeks after.

Among those in the Nubeqa arm, analyses evaluated the association between undetectable PSA at weeks 24 and 36 with overall survival and time to PSA progression.

Future Direction

To address existing questions around quadruplet regimens in metastatic hormone-sensitive prostate cancer, as well as barriers to getting patients to achieve undetectable PSA, Saad noted that clinical trials will be key.

“We're going to try to use genomics, use everything we have to try to understand what is that extra therapy? Because we can’t keep doing trials where we just give everything to everybody all the time,” he said. “And I think we're going to take a more rational approach to what we decide to give. And these patients that are not getting great responses must have something that's driving the tumor that's making it upfront resistant.”

Similarly, he added that umbrella trials will be the next step in evaluating treatment options for this patient population.

“We need to start doing umbrella trials where we take patients and then we start putting them into [trials] and see if we can we get from detectable to undetectable and say, ‘OK, well this is maybe a way we should be designing other phase 2, phase 3 studies.’ And we're doing these umbrella trials, we're trying to look for signals.”

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