New Precision Medicine Approaches in Advanced Prostate Cancer
In the fourth video of the series, Jorge Garcia, MD, FACP, considers PSMA-positive cells as a therapeutic target in men with metastatic castration-resistant prostate cancer and discusses the implications of the VISION trial for the therapeutic landscape.
[M]any of us recognize th[e] lack of biomarkers for prostate cancer….[C]ertainly PSA, prostate specific antigen, is a decent biomarker, but it becomes very imperfect when you develop castration-resistant disease. So…PSMA becomes an important target for us because PSMA is [a] transmembrane carboxypeptidase [that] is highly expressed in prostate cancer including metastatic lesions. [It] is a very specific…target [that]…has a really restricted [relative] expression—or what I would call [a] normal expression—mainly [in] salivary and lacrimal glands. [T]herefore, [LuPSMA has a] low likelihood of causing…systemic side effects….In addition to that, I think that PSMA is an excellent target for PET imaging.
The standard of care for men with metastatic prostate cancer in the castration-sensitive or naive space is simple…[it] historically…has been androgen deprivation therapy. The challenge is the longer those men live suppressed on testosterone, the more likely [it is] for them to become castration resistant….“[C]astration resistant” [has] a very simple definition; it requires for you to have a rising PSA and/or evidence of clinical progression. [I]f you indeed have metastatic disease, when you develop…a rising PSA, radiographic progression, and/or symptomatic progression,…in the absence of male hormone (which is defined by a testosterone level less than 50), that makes you fit in the definition for castration-resistant disease.
[T]he standard of care for those men is quite large today in North America. We have over 7 lines of therapy that are…life-prolonging agents….[W]hat I think is important to understand is…there are many lines of therapy that our patients can receive, yet the sequence of such agents is not well understood;…we don't understand [the] mechanisms of resistance.
VISION was a very specific trial. Patients were in fact required to have a PSMA-positive PET. Now,…I think most of us in the field realize that whole body bone scans using technetium-99 and CT [computerized tomography] scans of the chest, abdomen, and pelvic region…have become obsolete, for the most part….[W]ith the approval of PSMA PET in North America this year, I think the field will move quite rapidly into that space. It is now part of the NCCN [National Comprehensive Cancer Network] guidelines. And I think that…[in] the next year to 5 years, we're going to be…using PSMA PETs right and left to…define how we…treat our patients.
[T]he primary end points used [in VISION] were what they call…alternative primary end points. And that simply meant, as Mike Morris presented at ASCO this year,…that the study…would have been positive if either or both primary end points were significant. So the important part of this is that if you look at the primary end point [of overall] survival, the hazard ratio…in that trial was 0.62, which…means [a] 38% relative risk reduction of dying from prostate cancer if you receive lutetium PSMA, against the control arm…run out, [to 15.3 months and 11.3 months, respectively, with a difference of] around 4 months between the 2 arms….If you look…at the [other primary end point of] rPFS in the prolonged survival, just for this set of patients who actually had rPFS analysis, that also actually met their primary end point with a hazard ratio 0.6.
[T]he important part is this is a hazard ratio that is consistent with all hazard ratios that we have seen in that space. Remember, the hazard ratio put survival in all the ORIOLE trial and the radium-223 and in the chemotherapy trials…between 0.6 and 0.5, if you will, to 0.79. So [it’s] really consistent with an improvement in outcome for these patients.
And now we're going to have to start paying more attention to the side effects, as these can be quite cumbersome to manage. [T]here are some unique side effects that are important for us to be aware of. They have to be learned—I shouldn't say learned, because medical oncologists do this—but certainly [we need to] be a little bit more in tune with [them], as we're not accustomed to see[ing] them drastically with the standard chemotherapies that we use, or for that matter, with the oral agents that we're using in that space.
[In the end,] lutetium PSMA becomes…one of the most attractive therapeutic targets in the field for men with castration-resistant prostate cancer. I don't think the future could be more exciting for our patients, for all of us who do drug development in prostate cancer. I think we have accomplished quite a bit in the last 7 years [and] have drastically changed how we manage our patients. And I think the future is bright for the field, and certainly for our patients, which is the primary reason why we do what we do.