The addition of the AKT inhibitor capivasertib (Truqap) to abiraterone (Zytiga) and androgen deprivation therapy (ADT) improved radiographic progression-free survival (rPFS) in patients with PTEN-deficient metastatic hormone-sensitive prostate cancer in the phase III CAPItello-281 study presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium.
In this exclusive MedPage Today video, Daniel J. George, MD, of the Duke Cancer Center in Durham, North Carolina, discusses the efficacy findings and unique disease biology, and what patient-reported outcomes (PROs) reveal about early toxicity and longer-term tolerability.
Following is a transcript of his remarks:
Just as way of background, in normal prostate cancer, the androgen receptor drives this biology. And in PTEN deficiency, we have activation of the AKT pathway, a parallel pathway, which can drive progression independent of the androgen receptor.
Capivasertib is an AKT inhibitor, blocks all isoforms. It’s FDA approved in breast cancer, and we studied it in prostate cancer in this setting, and it met its primary endpoint, had an improvement in the radiographic progression-free survival in these patients of 7.5 months.
Importantly, the control arm, abiraterone/ADT was only 25 months median rPFS, so shortened from what we would expect in other unselected populations.
Overall, we saw secondary endpoints. Overall survival, there was no difference. There’s a slight trend in favor of capivasertib, but nothing statistically significant. Other secondary endpoints were done as just supportive of these data, and we saw symptomatic skeletal event rates were lower in our capivasertib arm. Hazard ratio was around 0.78 or so. And the same with the time-to-castration resistance, and that’s a composite endpoint of skeletal events, rPFS, death, and PSA [prostate-specific antigen] progression.
What’s interesting is that when we looked at PSA progression, it was a much slower incidence. So we saw a hazard ratio of 0.73 in favor of capi [capivasertib], but what we saw was most of the events for castration resistance were without a documented PSA progression. And that’s really important. It’s a different biology than what we’re starting out with in this disease. And it’s important to recognize that value and all these symptomatic skeletal events that go with it.
Now, the patient-reported outcome data were really interesting. We do see from a physical domain perspective, there’s a decline in the first 3 months in the capi arm versus the abi [abiraterone]/placebo arm. But after that, the curves are parallel, and we see the same degree of these deterioration and physical well-being rates in both arms, suggesting that after your initial first 3-month period, from that point on, we don’t really see cumulative effects of the capi.
It’s pretty much all driven by the abi/ADT. So when we look in those first 3 months, that’s where we see our side effects. Our onset of diarrhea, of rash, and hyperglycemia all happen in that window. So it’s just important to recognize that’s where we make our interventions. Eighteen percent of patients have to discontinue because of treatment side effects from the capi, so recognize some of these patients have to stop therapy, but the majority don’t. And we’re able to modify dose, hold drug, lower the dose in order to get them on a dose they continue. And that’s the upshot.
From that point on, we see everything’s the same. And the overall PROs, the functional PROs, no effect of this physical well-being, it was only in the physical well-being domain.
So, in summary, I think capi definitely improves the rPFS. We see a number of secondary important endpoints improved with capi in this population.
And we see a side effect profile that’s known with this drug on target and manageable within the first 3 months for most patients. And people can decide how much of that is really worth it in their patients, but it’s a good option for these patients who have PTEN deficiency.
Source: Read Full Article
