Case 1: The Importance of PSA Doubling Time in Prostate Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Neal Shore, MD, FACS:Ken, your thoughts on the role of PSA [prostate-specific antigen] doubling times when deciding on when to start treatment? And maybe it’s not just in nmCRPC [nonmetastatic castration-resistant prostate cancer], but in biochemical relapse, in general.

Kenneth Kernen, MD:I think PSA doubling time is really critical. We didn’t think about it for a long time. We probably all thought about it maybe 20 years ago it. It was important, but then it kind of just went away. And now, I think it’s really critical. If someone has a doubling time of less than 10 months, or around 10 months, we know this is a clinically relevant change. He’s got clinically relevant disease. If his PSA doubling time had been a couple of years, or 4 years, and maybe there’s just a little bit of benign tissue left behind, that’s a different animal. But clearly, the doubling time of under 10 months is definitely something we want to treat and be more aggressive with. We know that if we don’t, that time to metastatic disease is much less.

Neal Shore, MD, FACS:Let me ask you, Jorge, or Alicia, if you want to chime in on this, we really have some good, prior trials that showed that this PSA doubling time calculation of 10 months or less, which inform the 3 trials. Maybe one of you would like to talk about some of the early work that Matthew R. Smith, MD, PhD, had done? We’ve done some work. All of us were, I think, involved in this notion around the doubling time and how it affected the likelihood for developing metastases.

Alicia Morgans, MD:I completely agree with you, and I think that we all are familiar with Matthew Smith’s data published in theJournal of Clinical Oncologya number of years ago. It was a phase III clinical trial of denosumab for the prevention of metastatic disease in men with nonmetastatic CRPC. So, it was really thinking about this particular population. And in that data we could see a very clear association between a decreasing PSA doubling time and an increased risk of metastatic disease or death from prostate cancer. And really, it was interesting that there was an inflection point somewhere between 8 and 10 months, where the curve really took off in that particular dataset. I think that solidifies, particularly in the nonmetastatic CRPC population, the importance of this doubling time, though, of course it was defined in natural history cohorts too. Jorge, I don’t know if you want to share any of that data?

Jorge Garcia, MD:We all agree that doubling time is a super important surrogate marker for survival and time to metastases. But if you go back in the history of this case, you can probably select pieces of the patient that are also telling us, as clinicians, the importance of early, aggressive, if you want to call it that, management. The fact that he has a strong family history of other cancers will raise a flag right now for us. Maybe he has a DNA repair deficiency that would increase his risk of having pretty aggressive disease?

Secondly, the fact that he had pretty aggressive disease. He had positive margins, but his inability to achieve an undetectable PSA also is telling to me. Whether or not you agree to early radiation or to defer radiation therapy, I think we have compelling data demonstrating, as imperfect as the data from Edward M. Messing, MD, were back in the 1990s, that early ADT [androgen deprivation therapy] for this patient population may, in fact, impact outcome in a positive manner. I do agree that early treatment becomes challenging when you look at the adverse effect profile and the impact on quality of life on suppression of testosterone.

But I think for most of us, the bigger controversy in the field has been the timing of initiation of ADT. It is that controversy that actually is applicable to this patient, because if this patient had been followed with serial PSAs and waited until he developed metastatic disease, we wouldn’t have seen M0 CRPC. So by default, and you mentioned that, Ken, we induce his state of migration, right? We induce his CRPC by initiation of ADT early, therefore inducing CRPC. So, I think doubling time is absolutely critical today, as you point out, Ken. But I think the history of this patient is also quite telling, that his time to biochemical progression, and time from biochemical progression to castration-resistant disease, is pretty tight. It’s pretty close, telling you that this patient does have, in fact, progressive disease.

Neal Shore, MD, FACS:Spot on. Right. He had aggressive histopathology. He had positive margins. When he got started on his ADT, he had a very short time before he became castration-resistant. And, the doubling time is pretty rapid. The earlier work done by Matthew Smith and others, we did the Amgen trials, and we actually had an ODAC [Oncologic Drugs Advisory Committee] on this. It was interesting. The bone metastases-free survival [BMFS] met its endpoint, yet the drug wasn’t approved. And interestingly, having been there, they went around and polled everybody at the panel, at the ODAC, and they said, “Well, what do you want to see?” Interestingly, they said, “We want to see about 2 years. We want to see 2 years.” And the BMFS for that particular trial, which met its endpoint and was statistically significant, was only about 4 months, 6 months, when it was really enriched.

Transcript edited for clarity.