Over the last decade we have known from preclinical data and some clinical trials that there is a cooperative interaction between AR targeting and PARP targeting, so the poly (ADP-ribose) polymerase enzyme, which is involved in DNA repair, and the AR, androgen receptor, pathway. So if you inhibit both pathways at the same time they may cooperate with each other and enhance the efficacy of each other regarding anti-tumour action.

So from that perspective several trials have been done in late phases of prostate cancer or metastatic prostate cancer. If you look at the TALAPRO-2 trial, for example, it was a combination of enzalutamide plus talazoparib, an ARPI and a PARP inhibitor, compared to enzalutamide alone in patients who had metastatic castration-resistant prostate cancer, and nowadays we are using the words metastatic androgen pathway modulation resistant prostate cancer, so metastatic APMR disease, to avoid the word castration. In this context, there was an improved overall survival in patients with metastatic APMR or mCRPC and the benefit was enhanced in those patients who had HRR, or homologous recombination repair gene alterations. There was a 14 month improvement in overall survival when you combine enzalutamide plus talazoparib versus enzalutamide alone in the mCRPC setting in patients with HRR gene alterations.

Over time we have seen ARPIs moving to upstream. Many patients in the US and the rest of the world are diagnosed with metastatic hormone-sensitive prostate cancer or APMS prostate cancer and enzalutamide or other ARPIs are very frequently used in this setting.

So that’s one piece of background information. Second, we also reported in the BRCAAway trial that combining these treatments may be more effective than sequencing these treatments. So an ARPI followed by PARP inhibitor may not give you the same kind of benefit as combining them upfront. So if you just look at the preclinical rationale, the background from the mCRPC setting, it provided the rationale for using this combination in the metastatic hormone-sensitive prostate cancer setting.

So in this clinical trial, in the TALAPRO-3 clinical trial, patients who had newly diagnosed metastatic prostate cancer, mHSPC, CSPC or APMS now, with HRR gene alterations, and they were prospectively assessed, central testing, so very rigorously tested. These patients were included in this trial, a total of 599 patients. So almost 600 patients were randomised to ADT plus enzalutamide plus talazoparib versus ADT plus enzalutamide plus placebo. Blinded trial, a rigorously done trial. Radiographic progression free survival was the primary endpoint. A key secondary endpoint was overall survival, it was alpha protected, meaning the trial had the power to detect overall survival if rPFS was positive. So it was a hierarchical testing, so if rPFS is positive then we would look for OS, which is the case now. Then multiple other secondary endpoints such as time to PSA progression, time to subsequent antineoplastic therapy such as chemotherapy, and quality of life, and several others.

Randomisation was 1:1 and it was stratified by presence of de novo metastatic disease versus relapsed metastatic disease. We also included high-volume versus low-volume disease and we also had a stratification factor of looking at BRCA mutations versus non-BRCA HRR gene alterations to make it more rigorous.

So let’s look at the primary results first. If we look at rPFS it was significantly improved in the combination arm of enzalutamide plus talazoparib versus enzalutamide plus placebo. It was not only statistically significant but also clinically meaningful. There was a 52% reduction, so almost half, 52% reduction in risk of disease progression or death with the combination arm. The hazard ratio was 0.48 favouring the combination of enzalutamide plus talazoparib. If you look at the median progression free survival, or rPFS, in the enzalutamide arm it was  45.8 months. That means this is a very active control, very active drug, which we know from the past. But to build upon that active control with a risk reduction of rPFS, progression or death by 50% is really remarkable.

If we look at overall survival, in fact most patients are actually still receiving treatment. Most patients have not progressed and also most patients are still alive, which is great news for our patients. The overall survival data is immature right now but with the level of events we have there’s a trend which favours the combination arm, so enzalutamide plus talazoparib continues to do well from an overall survival perspective also. But the trend is not significant because of a low number of events and the hazard ratio is 0.77 favouring the combination arm.

If we look at other clinically meaningful secondary endpoints, such as time to PSA progression, which is very meaningful to our patients, and time to subsequent antineoplastic therapy, including chemotherapy, we also favour the combination arm with a hazard ratio of 0.51, again an almost 50% reduction in risk of PSA progression or receipt of subsequent therapy including chemotherapy. As I said, most patients are still receiving the treatment so still have not progressed. So very small numbers but the most commonly used next line therapy is docetaxel which is good news, meaning patients are receiving treatments which are effective. The next most common therapy in the control arm is olaparib, which is a PARP inhibitor.

Now, the next question comes on quality of life. Yes, you are delaying disease progression very significantly but how is it affecting the quality of life? We used EORTC QLQ-C30, this is a standard validated questionnaire. We looked at global health status, quality of life, physical functioning, role functioning. So there was no clinically meaningful different in patient-reported outcomes between the talazoparib plus enzalutamide arm and placebo plus enzalutamide arm, except appetite loss per EORTC QLQ-C30. Which is great news, meaning quality of life is preserved while patients are receiving two therapies. Quality of life, as we know, is the sum of anti-tumour action and the side effects of the drug. So if you really enhance efficacy that somehow is able to counter the side effect because progressing prostate cancer also has side effects – fractures, bone pain, even death. So from that perspective this is great news for our patients.

That’s a nice segue to the side effect profile. If you look at the side effects, 79% of patients had treatment-emergent grade 3 side effects in the combination arm and 41% of patients had grade 3-4 adverse events which were treatment emergent, meaning after starting the treatment, in the control enzalutamide arm. If you dissect the side effects it was dominated by anaemia. So 51% of patients had grade 3-4 anaemia which dominated the side effects. But if you look at other grade 3-4 side effects, most of them were in single digits and these are more common, more associated with adverse impact on quality of life. For example, fatigue grade 3 or GI side effects – nausea, vomiting, gastrointestinal side effects – they were pretty much in single digits which is great news.

Because anaemia is so common I’d like to delve deeper into anaemia and I’d like to elaborate on anaemia. I’d like to point out first that 43% of these patients had grade 1-2 anaemia at baseline. Grade 3-4 anaemia happens early on this treatment. So the median time to onset of grade 3-4 anaemia is actually 3.2 months and it’s not cumulative. So after 13 weeks you see the incidence of grade 3-4 anaemia going down and protocol-mandated dose reduction of talazoparib after the first episode of grade 3-4 anaemia. Once you reduce the dose patients seem to tolerate talazoparib well, as evidenced by a similar duration of talazoparib therapy in patients who developed grade 3-4 anaemia versus who did not. So if we look at the duration of talazoparib therapy, it was 34 months, almost three years, in patients who initially developed grade 3-4 anaemia and 35.9 months, almost 36 months, in patients who did not develop grade 3-4 anaemia. And only 5% of patients had to discontinue talazoparib because of anaemia.

So the message here is follow these patients frequently with monthly haemoglobin levels for the first three, four, five, six months. In frailer patients, in real-world patients, follow them maybe every 15 days. They don’t have to come to the doctor’s clinic, they can do a haemoglobin testing locally and the results can be sent to the doctor’s clinic. If a patient is on the trajectory to develop grade 3-4 anaemia we can reduce the dose of talazoparib without having to wait for grade 3-4 anaemia. So unlike protocol we can actually use this approach in the real world.

So if we look at the overall summary, talazoparib plus enzalutamide led to a clinically meaningful and statistically significant prolongation of rPFS with a hazard ratio of 0.48 and a 52% reduction in risk of progression or death compared to a very active control of enzalutamide therapy. If we look at the overall survival it is interim, unfortunately. Most patients are alive but the hazard ratio is 0.77, trending in the right direction, favouring the combination. If we look at non-BRCA HRR gene alterations it was also quite impressive. So in the BRCA mutation subgroup 0.37 was the hazard ratio, translating into a 63% reduction in risk of progression or death. In non-BRCA gene alterations the hazard ratio was 0.57, a 43% reduction in the risk of progression or death. If we look at common non-BRCA HRR gene mutations such as ATM, CDK12, in the ATM mutation subgroup it was a hazard ratio of 0.58, a 52% reduction in the risk of progression or death. CDK12 mutation is known to be associated with particularly bad prognoses and in that subgroup we saw a hazard ratio of 0.27, a 73% reduction in the risk of progression or death. The time to PSA progression, time to subsequent antineoplastic therapy, both the risk was reduced by 50% with the combination. And the most common side effect is haematologic, which needs to be monitored for monthly lapse every month. And if you reduce the dose up front in those patients who are developing grade 3-4 side effects, these patients are able to receive talazoparib for an equal duration of time, similar duration of time. There was no clinically meaningful impact on quality of life.

So if you combine all of this the conclusion is that the addition of talazoparib plus enzalutamide or the addition of talazoparib to enzalutamide improves radiographic progression, meaning delay of progression or death in our patients with metastatic prostate cancer with HRR gene alterations, newly diagnosed metastatic prostate cancer. It is a potentially new treatment option for these patients and this makes NGS testing and germline testing in our patients who are newly diagnosed with metastatic prostate cancer more important than ever.

Did you look at other subgroups in this data?

We are seeing consistent improvement in rPFS and pretty much all subgroups. Obviously there are some small gene subgroups which are so few in number that it’s hard to really see how much is the radiographic PFS benefit. But ATM is a common mutation and we saw a hazard ratio of 0.48 and a CDK12 hazard ratio of 0.27. If you look at the PALB2 subgroup, they are a very small number of patients, but all 11 patients who are receiving the combination therapy have not progressed.

So ultimately this mHSPC or mAPMS remains a lethal disease, unfortunately. Patients will eventually progress and the key would be to find the mechanism of resistance – why these highly effective combinations are eventually failing our patients, how to mitigate side effects. For example, should we be checking vitamin B12, folate, iron levels in all patients who are starting PARP inhibitors? How do we sequence therapies after patients are failed by this treatment? So those are the questions which will be answered down the line.