Expert Discusses Data From First Positive Trial for PARP Inhibitor in Prostate Cancer

Alan Bryce, MD

Alan Bryce, MD

PARP inhibition with olaparib (Lynparza) improved radiographic progression-free survival (rPFS) in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) who had alterations in homologous recombination repair (HRR) genes, according to findings from the phase III PROfound trial presented at the 2019 ESMO Congress. This was the first positive randomized phase III trial reported evaluating a PARP inhibitor in men with mCRPC.

The PROfound trial enrolled patients to 2 cohorts. In cohort A, 245 patients withBRCA1/2or ATMalterations, markers of HRR, were randomized 2:1 to receive either olaparib (n = 162) or physician’s choice of abiraterone acetate (Zytiga) with prednisone or enzalutamide (Xtandi) (n = 83). In cohort B, 142 patients with alterations in the BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, orRAD54L, all of which are associated with HRR indirectly, were also randomized 2:1 to olaparib or the control arm.

The median rPFS in cohort A was 7.39 months in the olaparib arm and 3.55 months in the control arm (HR, 0.34; 95% CI, 0.25-0.47;P<.0001). The 12-month rPFS rate was 40% and 11% in the olaparib and control arms, respectively.

The objective response rate was 33.3% with olaparib and 2.3% with the hormonal therapies (odds ratio, 20.86; 95% CI, 4.18-379.18;P<.0001). The median time to pain progression was not yet reached with olaparib versus 9.92 months with hormonal therapies, representing a 56% reduction in the risk of developing pain (HR, 0.44; 95% CI, 0.22-0.91;&nbsp;P= .192). Median overall survival (OS) in the olaparib arm was 18.5 months versus 15.11 months in the hormonal arm. However, OS did not meet statistical significance due to crossover in 80.6% of patients.

An exploratory analysis demonstrated that patients withBRCA2mutations had the greatest benefit in cohort A. Additionally, patients with&nbsp;RAD51B, RAD54L, andCDK12alterations had a greater benefit in terms of rPFS in cohort B. However, investigators note these findings are preliminary.

In an interview withTargeted Oncology, Alan Bryce, MD, associate professor of medicine at the Mayo Clinic, discussed the significance of the data from PROfound for men with mCRPC. He also highlighted findings from the CARD trial and where the field is headed in terms of targeted therapies versus chemotherapies.

TARGETED ONCOLOGY: What would you say has been the most compelling data at the 2019 ESMO Congress in prostate cancer?

Bryce:In the prostate cancer space, the PARP inhibitor data are coming into fruition&nbsp;now. We saw the results from the phase III PROfound study of olaparib in prostate cancer with DNA damage response mutations. While we knew that the PFS end point was positive, we [are also excited about] the OS end point now. This [is] the first PARP inhibitor to show positive results in a randomized phase III study, and it should launch the era of targeted therapy in prostate cancer.

TARGETED ONCOLOGY: What were the expectations for this trial?

Bryce:In prostate cancer, as many as 20% to 25% of patients with metastatic disease will have a mutation in 1 of the genes in the DNA damage response pathway. In most patients, this will beBRCA2, most commonly, orBRCA1. Then there is a tail of other potential mutations in this pathway as well. For those patients, the PARP inhibitors, in this case olaparib, appear to be highly effective with response rates approximating 50%.

This will be an entirely new class of drugs in prostate cancer. This will add to the options of androgen deprivation therapy, other hormone therapies, chemotherapy, and radiation therapy. PARP inhibitors is a new class of drugs for this 20% to 25% of patients.

TARGETED ONCOLOGY: Is there anything unique about olaparib compared to the other PARP inhibitors in prostate cancer?

Bryce:We really don&rsquo;t know how olaparib will compare to the other PARP inhibitors yet, so there is niraparib (Zejula) and rucaparib (Rubraca) that are fairly far along in studies as well. Talazoparib (Talzenna) is also coming along. We will likely end up in a scenario where we will have multiple drugs with good data, and we will eventually get into a situation where we will have to compare these drugs and decide if there are meaningful differences between them. At this point, we just don&rsquo;t know. Olaparib is clearly first, so it will be nice to have at least 1 and we will see how the rest play out.

TARGETED ONCOLOGY: We are just entering this space of PARP inhibitor therapy in prostate cancer, but what other potential targets are there in this setting?

Bryce:There is a tail of mutations in prostate cancer which appear targetable. We participated in a report looking atCDK12-mutant prostate cancer. This is perhaps, 5% to 10% of prostate cancers, and in our data set, we were able to see that the response to traditional androgen pathway inhibitors, like abiraterone acetate and enzalutamide, was actually poor, compared to PARP inhibitors, as we see from the various studies ongoing, but there appears to be a good response rate to immunotherapy. In our report on 58 patients, there were 8 patients treated with immunotherapy and a 38% response rate to checkpoint inhibition, which is really the highest we&rsquo;ve seen from checkpoint inhibitors. This is a small data set, but there is a rationale for why CDK12 should predict for response to checkpoint inhibitors. That is because CDK12 regulates chromosomal stability, so when CDK12 is mutated, what we see is a generation of large tandem duplications and chromosomal rearrangements within the prostate cancer, which as we now know, is much more likely to lead to neoantigen production than just tumor mutational burden. It may be that this is a good biomarker for immunotherapy response in prostate cancer.

There are other potential targets that are certainly being evaluated. I do think that the era of targeted therapy in prostate cancer is just getting started.BRCA1/2may be just the beginning of that, certainly as the biggest targets, but there are others that we will continue to work on.

TARGETED ONCOLOGY: Even though there is this big push towards targeted therapy, chemotherapy still retains a role. Could you explain the CARD trial in that respect?

Bryce:Without question, cabazitaxel (Jevtana) remains a relevant drug in prostate cancer. It&rsquo;s clearly utilized less than we would expect when we look at the real-world data. It has been positioned in the post-docetaxel space, and with the approval of many new drugs—that is abiraterone, enzalutamide, the next-generation anti-androgens. The positioning of cabazitaxel and its overall uptake has been somewhat unclear, so now we are starting to get some data on what the actual response rate to cabazitaxel is now in the current setting. The old TROPIC data only reflected an era where docetaxel was the only prior therapy these patients would have received. We see that cabazitaxel has ongoing efficacy. It certainly has a role to play. It&rsquo;s the toxicity management that is going to be the challenge for physicians and figuring out where to position it in terms of the patient&rsquo;s fitness. That is the biggest question&mdash;can you give it to a patient in a sequence and at a timing that it would be tolerated well?

TARGETED ONCOLOGY: What is on the horizon that oncologists can look forward to in prostate cancer?

Bryce:There is a lot going on in the prostate cancer space. I think the most exciting has been the developments around PARP inhibitors, but radiopharmaceuticals, like lutetium, are coming along. We anticipate hearing those results in the future. The immunotherapy question in prostate cancer is still a riddle we haven&rsquo;t solved yet, but there is lots of work going on there. Multiple reports came out at ESMO, so we will continue to work on that question.

Advanced imaging, as well, may transform the field and the ability to detect disease at earlier states. There are also important questions about treatment around oligometastatic disease and primary [disease] are being addressed at this time.

Reference:

Hussain M, Mateo J, Fizazi K, et al. PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations. Presented at: ESMO Congress 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA12_PR.