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Neeraj Agarwal: Hi, my name is Dr. Neeraj Agarwal. I'm a professor of medicine and director of Genitourinary Oncology Program at the Huntsman Cancer Institute, University of Utah. Today, I'm so pleased to have Dr. Gert Attard, professor and medical oncologist from the University College of London. Welcome, Gert.

Gerhardt Attard: Thank you, Neeraj, for asking me.

Neeraj Agarwal: Yeah, and for first of all, congratulations, huge congratulations to you for presenting the results of one of the most awaited clinical trials in metastatic hormone sensitive prostate cancer, the AMPLITUDE trial in the ASCO 2025 meeting. Could you please tell us, why did you do this trial?

Gerhardt Attard: Yeah, thank you. I mean, that's kind. It was a great honor to present the trial. So as many of your listeners will know, cancers with-- prostate cancers with a gene defect or a defect in a gene involved in homologous recombination repair are sensitive to PARP inhibition. And we have had approval for PARP inhibitor monotherapy after progression on an androgen receptor pathway inhibitor for, I guess, four or five years now.

And you and I will have treated many patients with alterations in these genes, and especially with BRCA, which accounts for about half of them. And these cancers are sensitive to PARP inhibition. But resistance often develops quite quickly.

In fact, for most of-- for the two seminal trials, the radiographic progression free survival is less than 12 months. So the hypothesis here is if we use PARP inhibitors earlier in combination with androgen receptor pathway inhibitors, will that be effective and help our patients? Now, PARP inhibitors have been combined with androgen receptor pathway inhibitors, as you know well, from the seminal TALAPRO-2 trial that you co-ran.

They work in mCRPC. But we rarely use ARPIs for mCRPC. And as patients progress into mCRPC, they can become unwell and miss the chance for the next line of treatment. Over the past decade, in fact, 11 years ago, I think, we first saw data from the CHAARTED trial, showing using docetaxel upfront rather than waiting till castration resistant disease improved survival.

A couple of years later, I think it was 2017, we saw similar data for abiraterone from the LATITUDE and STAMPEDE trials. And then we've seen that for several other androgen receptor pathway inhibitors. So we now have this backbone of care, ADT plus ARPI, plus or minus docetaxel. And for some of our patients, we're using all three.

There's a poster here at ASCO presented by doctors Olmos and Castro. You may have interviewed on the CAPTURE study. The CAPTURE study is a large Spanish observational prospective study. It very convincingly shows that cancers with mHSPC or mCSPC that have alterations in HRR or BRCA have worse outcomes.

So here we have a group of patients who are treated with ADT, ARPI plus or minus docetaxel, but who have poor outcomes and who harbor a lesion that makes them sensitive to PARP inhibition, of course, through synthetic lethality.

So the AMPLITUDE trial randomized mCSPC patients with cancers harboring an alteration in an eligible HRR gene, the most common is BRCA. That accounts for about half the patients. And randomized those patients to either niraparib or placebo. And the backbone is ADT abiraterone acetate with prednisone.

The trial has met its endpoint, I guess, which is why you're excited about it. The study shows an improvement in radiographic progression free survival by 48% in the BRCA group. So the hazard ratio is 0.52. That met the pre-specified endpoint.

And then the HRRm group, and the hazard ratio is 0.63. So clear evidence of efficacy, clear evidence that starting a PARP inhibitor upfront for this group of patients is effective and delays time to progression of that, probably more effective in the BRCA mutants. And we repeatedly have these discussions.

In the non-BRCA mutant group, the hazard ratio is 0.81. So I think there is activity there. But it's likely to be heterogeneous. In the BRCA population, this is very clear.

Neeraj Agarwal: So how many patients were enrolled on the trial?

Gerhardt Attard: Close to 700.

Neeraj Agarwal: So you are saying BRCA1 and BRCA2 were about half of these patients?

Gerhardt Attard: Correct, correct. So about 6,000 were sequenced in the screening phase. The trial allowed local tests, so locally determined HRR alterations. And also, there was a concurrently running study called PREVALENCE, which was testing for the same genes in an observational feasibility study.

So some patients came in through PREVALENCE. Some had local tests. The vast majority were detected by the central testing provider provided by-- as part of the trial, yes, leading to randomization of 700 patients. One to one, equal numbers in both groups.

Neeraj Agarwal: So trial met the primary endpoint, which is great news for our patients and for the investigators, equally. I would say it takes years of efforts to do these kind of trials. What are the data on overall survival?

Gerhardt Attard: Yeah, good point, good point. So of course, key question. So there are two key secondary endpoints that were studied to have a graphical testing for efficacy. First, RPFS, then time to symptomatic progression, and then overall survival. And this is by molecular subgroups, BRCA first and then the whole intention to treat population, so all the HRRm.
So the first key secondary endpoint, time to symptomatic progression, that was statistically significant, and I think the most will agree, clinically significant. So reducing the risk of symptomatic progression by about half. OS is still immature. So about half the number of patients have had-- or we have halved the number of deaths that would be required for the final analysis.
However, in my opinion, the trend is looking promising. So the hazard ratio estimate for BRCA is 0.75. For the whole HRR, mutant intention to treat population, it's 0.79. That's, of course, not statistically significant.

Neeraj Agarwal: But it's immature.

Gerhardt Attard: It's immature. There's no evidence of detriment, which is a key question. And we'll talk about side effects and toxicity. Yes, and a very promising trend. About 36% of patients who were randomized to placebo received PARP inhibitor next. There was also some use of carboplatin, I guess because PARP inhibitors may not have been available throughout.
I think that's important. Having as close to best case scenario subsequent use of PARP inhibition. In the trial, of course, this is a double blind placebo controlled trial. So you can't really have crossover.

I don't think there's any trial, at least in prostate cancer, that has had crossover with a placebo control. But we did unblind patients once the primary endpoint was met. Those patients had the BRCA status.

So unlike the current situation for my patients who do not go on trial, when they develop mCRPC, I then need to get testing. And hopefully, the trial changes that. I know here in the US, you will often test up front. But in a lot of Europe, we cannot. The licensing and test directory requires that we wait for mCRPC. And we know the challenges with that.

Neeraj Agarwal: Absolutely.

Gerhardt Attard: Finding the tissue failure. So all our patients in our trial knew that-- the BRCA status was known. The HRR status was known. So I think we'll have a higher use of PARP inhibition post placebo. It's not going to be 100%. It never is. Even in--

Neeraj Agarwal: Usually, it's half of the patients who get any subsequent therapies.

Gerhardt Attard: Yeah, so we're actually running a bit more than that got a subsequent life-prolonging therapy. And of course, these are still relatively early days. So when the data's cut, some patients will have progressed within the past few months. They'll still be preparing for the next line of therapy. But again, speaking from personal experience, some patients, as you've said, become too unwell and never move on to the next one.

Neeraj Agarwal: Yeah, this is great. How about side effects you encountered?

Gerhardt Attard: So this comes at a cost. And that's why I believe this requires a precision approach in this disease setting, where patients are taking treatment for a long time. About 75% of niraparib patients versus 50% in placebo, had grade 3 or 4 adverse events, primarily anemia, high requirement for transfusion amongst that group, hypertension was the most common non-hematological cause. So there is a cost.

I'm somewhat reassured that when we look at treatment discontinuations due to toxicity, it's 15% on niraparib, 10% on placebo. Not to be ignored, but it's less than 5%. More patients are stopping treatment because of treatment-related toxicity.

There's one case of myelodysplastic syndrome in the niraparib group. And there were double the number of treatment related-- or deaths which occurred after a treatment related adverse event, so 14 with niraparib, 7 with placebo. I think this combination is a potential treatment option for this group of patients.

But it requires a discussion. I think for BRCA, it's probably clearer. For the non-BRCA requires a more nuanced approach because there's a cost. And this cost is side effects, toxicity, patients are requiring blood transfusions, so on and so forth.

Neeraj Agarwal: Well, thank you for such a great discussion on the results of the AMPLITUDE trial. And congratulations, Gert, to you and to your team for performing this trial over the last many years. And hopefully, this will lead to two things.

Number one, it will allow genomic sequencing in the metastatic hormone sensitive prostate cancer, which will allow our patients to get their genomic results, get to know the effect on their family members. Ultimately, it will lead to cascade germline testing, I believe. And of course, a new therapy which will impact their survival outcomes soon to be available in our countries. So congratulations, again.

Gerhardt Attard: Thank you.