PARP Inhibitors Gain a Foothold in Prostate Cancer

Alan Bryce, MD

Until strong findings emerged from the phase III PROfound study of PARP inhibitor olaparib (Lynparza) in patients with metastatic castration-resistant prostate cancer (mCRPC), targeted therapy had an uncertain foothold in this tumor type. Alan Bryce, MD, associate professor of medicine at the Mayo Clinic in Rochester, Minnesota, speculated that olaparib will likely herald a new class of drugs in the treatment of prostate cancer.

In an interview with OncLive, Bryce discussed the PROfound trial (NCT02987543) and its significance for the treatment of prostate cancer. Other PARP inhibitors are likely to emerge, backed by solid data, and investigations suggest that numerous molecular targets exist for which agents could be developed.

In the PROfound study, PARP inhibition with olaparib improved radiographic progression-free survival (rPFS) rates in heavily pretreated patients with mCRPC who had alterations in the homologous recombination repair genes BRCA1/2 and ATM. This was the first positive randomized phase III trial reported evaluating a PARP inhibitor in men with mCRPC (Table).^1,2

An exploratory analysis demonstrated that patients with BRCA2 mutations had the greatest rPFS benefit. Additionally, patients with RAD51B, RAD54L, and CDK12 alterations had a greater benefit in terms of rPFS.

Bryce also discussed the CARD trial (NCT02485691), in which patients with mCRPC who previously received docetaxel and abiraterone or enzalutamide were randomized equally to cabazitaxel (Jevtana) plus prednisone or another androgen inhibitor. Investigators concluded cabazitaxel significantly improved several clinical outcomes over androgen inhibition, including median imaging-based PFS (8.0 months vs 3.7 months), median overall survival (13.6 months vs 11.0 months), and median PFS (4.4 months vs 2.7 months).³ These findings make cabazitaxel a viable addition to the prostate cancer armamentarium, Bryce said.

OncLive: What were the most compelling data in prostate cancer at the European Society for Medical Oncology (ESMO) Congress 2019?

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

What were the expectations for this trial?

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. This will be BRCA2, most commonly, or BRCA1. There are other potential mutations in this pathway. For those patients, the PARP inhibitors, in this case olaparib, appear to be highly effective, with response rates approximating 50%.

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

Is there anything unique about olaparib relative to other PARP inhibitors in prostate cancer?

We really don’t know yet how olaparib compares with the other PARP inhibitors. Niraparib [Zejula] and rucaparib [Rubraca] are fairly far along in studies. 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’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.

Besides PARP inhibition, what other potential targets are there in prostate cancer?

A number of mutations in prostate cancer appear targetable. We participated in a report looking at CDK12-mutant prostate cancer.⁴ This is perhaps 5% to 10% of prostate cancers, and in our data set from various ongoing studies, we were able to see that the response to traditional androgen pathway inhibitors, such as abiraterone acetate and enzalutamide, was actually poor, compared with PARP inhibitors, but there appears to be a good response rate to immunotherapy.

In our report on 58 patients, 8 were treated with checkpoint inhibition and the response rate was 38%, which is really the highest we’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, we see a generation of large tandem duplications and chromosomal rearrangements within the prostate cancer, which 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. BRCA1/2 may be just the beginning of that. Certainly, these are the biggest targets, but there are others that we will continue to work on.

Although there is a big push for targeted therapy, chemotherapy still retains a role. Could you explain how the CARD trial highlights this?

Without question, cabazitaxel remains a relevant drug in prostate cancer. When we look at the real-world data, we can see that it’s clearly utilized less than we would expect. It has been positioned in the postdocetaxel space. With the approval of many new drugs—abiraterone, enzalutamide, the next-generation antiandrogens—the positioning of cabazitaxel and its overall uptake have been somewhat unclear, so now we are starting to get some data on the actual response rate to cabazitaxel. The old TROPIC trial [NCT00417079] data reflected an era when docetaxel was the only prior therapy patients with prostate cancer would have received. Cabazitaxel has ongoing efficacy. It certainly has a role to play. Toxicity management and patient fitness are going to be the biggest challenges: Can you give cabazitaxel to a patient in a sequence and at a timing that it would be tolerated well?

What other interesting developments in prostate cancer are on the horizon?

There is a lot going on in the prostate cancer space. I think PARP inhibitors have been the most exciting developments, but radiopharmaceuticals, such as lutetium, are coming along. We anticipate those results in the future. The immunotherapy question in prostate cancer is a riddle we still need to solve, but lots of work is going on there. Multiple reports came out at ESMO.

Table. Olaparib Doubles rPFS in Patients With BRCA1/2- and ATM-Positive Metastatic Castration-Resistant Prostate Cancer^1,2

Advanced imaging, as well, may transform the field and improve our ability to detect disease at earlier stages. Important questions are being addressed about treating oligometastatic disease and primary disease.

References

1. 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.
2. Klaassen Z. ESMO 2019: PROfound: phase 3 study of olaparib vs. enzalutamide or abiraterone for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations. Uro Today website. www.urotoday.com/conference-highlights/ esmo-2019/esmo-2019-prostate-cancer/115401-esmo-2019profound-phase-3-study-of-olaparib-vs-enzalutamide-or-abiraterone-for-metastatic-castration-resistant-prostate-cancer-with-homologous-recombination-repair-gene-alterations. html. Accessed November 18, 2019.
3. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer [published online September 30, 2019]. N Engl J Med. 2019. doi: 10.1056/NEJMoa1911206.
4. Antonarakis ES, Velho PI, Agarwal N, et al. CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, PARP inhibitors, and PD1 inhibitors. Ann Oncol. 2019;30(suppl 5):v325-v355. doi: 10.1093/annonc/mdz248.