Utilization of PARP Inhibitors in Prostate Cancer

Rohan Garje, MD

New developments like the combination of PARP and androgen receptor-signaling inhibitors have helped shape the treatment landscape for patients with metastatic castration-resistant prostate cancer (mCRPC).

Two trials specifically—PROpel (NCT03732820), a phase 3, randomized, placebo-controlled, global, double-blind trial, and TALAPRO-2 (NCT03395197), a phase 2 study—have shown significant improvements in outcomes for this patient population.

Recently, the FDA approved new combinations studied in these trials for the treatment of patients with mCRPC. These combinations include olaparib (Lynparza) in combination with abiraterone (Zytiga) and prednisone or prednisolone for adult patients with mCRPC, and talazoparib (Talzenna) with enzalutamide (Xtandi) for patients with mCRPC that have homologous recombination repair (HRR) gene alterations in their disease.

“Previously we had monotherapy options with olaparib and rucaparib [Rubraca]. Now we have combination options with PARP inhibitors, specifically with enzalutamide and talazoparib, and there's a combination therapy approved for olaparib that abiraterone acetate and also niraparib [Zejula] with abiraterone,” Rohan Garje, MD, told Targeted Oncology^TM, in an interview.

In the interview, Garje, chief of genitourinary oncology at the Miami Cancer Institute, discusses current treatment options for patients with prostate cancer and the role of PARP inhibitors.

Targeted Oncology: Can you discuss some of the treatment options that are currently available for patients with prostate cancer?

Garje: In the last few years, we have seen significant improvement in the treatment options we have for prostate cancer. There are a lot of drugs that were approved in metastatic castrate-resistant prostate cancer which have now moved into the metastatic castration-sensitive setting, so that's exciting.

When we look into prostate cancer treatment options, we do a broader grouping. We have options with novel androgen receptor pathway inhibitors, we have chemotherapy agents with docetaxel and cabazitaxel, and then now, we have more nuanced approaches based on targeted therapeutics based on the presence or absence of homologous recombination repair gene mutations, especially BRCA1 and BRCA2, and we do have options with PARP agents. It is exciting to have 3 new updates coming up these past few months and approvals as well.

Previously we had monotherapy options with olaparib and rucaparib [Rubraca]. Now we have combination options with PARP inhibitors, specifically with enzalutamide and talazoparib, and there's a combination therapy approved for olaparib that abiraterone acetate and also niraparib [Zejula] with abiraterone. This is definitely exciting. Then moving beyond PARP inhibitors, we do also have approvals for radioligand therapeutics for patients with advanced prostate cancer.

Would you discuss the TALAPRO-2 study of enzalutamide and talazoparib and how that's created a new standard of care?

TALAPRO-2 was primarily evaluating the combination of talazoparib, which is a PARP inhibitor, along with enzalutamide in patients with metastatic castration-sensitive prostate cancer in first-line setting. Most of the patients were anti-androgen naīve, or they could have received anti-androgens in the past but not progressed on it, because nowadays we use anti androgens in the adjuvant setting for high-risk patients after a surgery or radiation therapy. In this study, the patients included were both HRR-positive and -negative and we clearly showed that the benefit was for HRR-positive patients, and specifically, benefit was seen for BRCA1 and BRCA2 mutated patients.

The overall survival data are still immature and with regards to the benefit, what we have seen is primarily in radiographic progression-free survival. The hazard ratios were significant where patients who had her HRR-deficient tumors, which included a spectrum of not only BRCA1 and BRCA2, but additional mutations that all had a radiographic progression-free survival benefit compared with patients who received placebo with enzalutamide. Based on these study results, the FDA [recently] approved the combination for patients with HRR-mutated or -deficient metastatic castration-resistant prostate cancer.

Can you discuss some of the PROpel study data?

The PROpel study was also in the similar space of patients with metastatic castration-resistant and they were in the first line of treatment with similar cohorts of patients who had HRR-mutant and non-mutant disease. In this study, the combination therapy was with olaparib along with abiraterone. We saw that there was, again, survival benefit primarily with BRCA-mutated patients, and also with other HRR-mutated patients. There was no benefit seen in filled [patients] with non HRR-mutated patients.

Based on these data, which required little bit additional evaluation when FDA was reviewing it, especially in the ODAC committee, upon deep review of this information, BRCA1- and BRCA2-mutated patients were found to have real benefit with this combination therapy. There were a lot of discussions about other mutations other than BRCA1 and BRCA2, but at the end, the FDA decided to approve it, specifically for BRCA-mutated patients. This is an exciting option for our patients and adds additional options for patients with advanced metastatic prostate cancer.

Can you discuss some of the treatment considerations when using PARP inhibitors for these patients? Who's best suited for these therapies?

One important thing is the patients need to be tested. That is the first step to consider these choices, because we have evidence to show that the patients with advanced prostate cancer are not getting next-generation sequencing for identification of these mutations. That is the first task for physicians, to test their patients to see if they have any of these mutations so that they can benefit with the combination therapy.

My goal has been to get all my patients who have advanced prostate cancer, metastatic prostate cancer, to make sure they get the next-generation sequencing to see if they have any of these HRR mutations. Now, if they didn't receive anti-androgen therapy during their castration-sensitive phase, for sure this is a combination therapy that should be considered. We recommend checking BRCA1/2 and other HRR mutations. It's difficult to pick between the 3 options which are currently available, that is with either niraparib, enzalutamide, or olaparib combinations. All 3 are unique PARP inhibitors. They may have nuances that partner drugs are different, so sometimes it depends upon access, it depends upon potential toxicities that the patients are willing to take are avoided, and at the same time, drug interactions. There may be some drug interactions, which may favor 1 drug over another drug. So those are the different clinical considerations because we don't have to add clinical trial comparison of all these combinations. We do utilize 1 of these agents based on these aspects of availability, access, insurance approval, drug interactions, and what [adverse events] we want to avoid for our patients.

When the patients are on the combination therapies, specifically with PARP inhibitors, we do know they are known to be myelosuppressive, especially when we identify these changes to happen in the initial 3 months of therapy. It's critical to keep a close eye on the white blood cells, hemoglobin, and platelets so that we ensure that they don't seriously decline on those numbers and do appropriate supportive care for those reductions or modifications to ensure better tolerability. That is 1 critical thing, but definitely the big goal is to make sure we present this as an option for patients who are entering into the first-line setting of metastatic castrate-resistant prostate cancer so that they get the best outcomes for the cancer.

What insights do you have on managing adverse events with PARP inhibitors?

The 3 to 4 main things we look into are that we keep track of the blood counts. If there is a significant drop in hemoglobin, we do recommend some temporary treatment breaks and transmission as appropriate. That is 1 important aspect. Then the same thing with platelet counts. There is a significant drop. We do recommend reductions as appropriate based on the grade of the drop in the platelets. The other thing, if the patients have appetite changes or nausea, or vomiting, is appropriate supportive care for that. Some patients may notice minor elevation in creatine. It may not specifically be due to worsening renal function, but it's just due to the mechanism the way these drugs work. Ensuring hydration and then close monitoring.

For all the PARP inhibitors in the initial 2 to 3 months, we do recommend checking blood work, including complete blood counts, kidney function, and liver function at least every 2 weeks for the first 2 or 3 months to make sure they're all in normal range or if they are affected, then do more close monitoring based on the situation.

Is there any ongoing research that you think could potentially be practice changing?

We are seeing a lot of new directions with androgen receptor degraders. They're still in early stages, but definitely the early-stage data are promising. The other thing which I'm keen on is biomarker-driven studies where the AKT inhibitors, the PIK3CA mutation-directed treatments are ongoing. That is another newer direction. Then combination strategies. The combinations with PARP inhibitors with other agents and beyond androgen receptor pathway inhibitors such as PARP inhibitors with chemotherapy and PARP inhibitors with lutetium agents are exciting options. Novel radioligand therapeutics beyond lutetium [lutetium Lu 177 vipivotide tetraxetan; Pluvicto]. We are now looking into other options as different choices, so it is definitely exciting.

Most recently, we also had a press release of atezolizumab with cabozantinib which met their primary end point. We are waiting for those results, so that could also be potentially practice changing soon. [We are] excited for the field of prostate cancer and in the next year, we are hoping to see much more further development, and in the next 5 years, [anticipate] several new novel agents to come up.

What unmet needs still remain in the space?

It's exciting to see all these new treatments coming up which start in the castration-resistant phase and then slowly move into castration-sensitive phase, but still, we need the biomarker-driven approaches beyond PARP inhibitors. We have seen a lot of improvements, but patients still experience progression. We need to know why they develop resistance to PARP inhibitors. Is there any way to overcome that? Are androgen driven pathways still the main treatment modalities? How do we overcome resistance to anti-androgen therapy? That is another big direction we need to figure out so that this would continue to help our patients.

What advice do you have for community oncologists treating patients with prostate cancer?

The field is rapidly advancing and several new treatment choices are coming up. It is important for colleagues who practice a broad spectrum of oncology to catch up on these changes. There were 3 new FDA approvals in the last 6 months. It's exciting to catch up on this. It's also important for them to understand the prerequisites to make sure that patients get the testing done to identify those mutations, because that is the first step for them to offer these therapies for patients.