Prostate Cancer Therapy: Insights into the Potential Role of PARP Inhibitors

This article is adapted from a teleconference that took place on January 27, 2020, and reflects the state of PARP at that time. A new teleconference that will update this data is scheduled for May 28, 2020.

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The clinical approach to prostate cancer has not yet been largely defined by patients’ genetics. However, poly (ADP-ribose) polymerase (PARP) inhibitors, which have evolved a role in the treatment of other forms of cancer, may alter the way physicians and patients view their therapeutic options going forward.

In the context of advanced prostate cancer, the first-line therapeutic approach is androgen deprivation therapy (ADT). If the cancer has metastasized to a distant location, ADT may be coupled with another therapy that inhibits the androgen receptor, such as apalutamide, enzalutamide, or with abiraterone acetate, which suppresses androgen production. There new agents are collectively termed next-generation hormonal agents (NHAs).

Those who received hormonal therapy early in the disease progression prior to metastases, when they develop castration resistance may be candidates for apalutamide, enzalutamide, or darolutamide. If these patients reach the metastatic state, and received one of these NHAs prior, they have already failed an NHA, so the challenge arises of which therapy to offer next. It is at this stage that PARP inhibitors become relevant, and their potential value may be weighed against that of alternatives such as chemotherapy and immunotherapy, like Provenge.

Below is a discussion of the potential and relative value of specific PARP inhibitor therapies in the treatment of prostate cancer.

Approval Analysis

In January 2020, the U.S. Food and Drug Administration (FDA) granted Priority Review to two PARP inhibitors for their use in prostate cancer: AstraZeneca’s olaparib and Clovis’ rucaparib, also known by their trade names Lynparza and Rubraca, respectively.

The FDA Will Likely Approve AstraZeneca’s Olaparib

The clinical data for olaparib, which is for patients with metastatic castration-resistant prostate cancer (mCRPC) and deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations who have progressed following prior treatment with an NHA, come from a randomized phase 3 trial.

According to the PROfound trial data, olaparib reduced the risk of progression or death by two-thirds in a cohort that included patients with BRCA1 and BRCA2 mutations, as well as those with the ataxia-telangiectasia mutated (ATM) gene. The hazard ratios for this cohort are impressive, and the data suggest that using olaparib would be much more useful than moving on to a second NHA.

The FDA Will Probably Not Approve Clovis’ Rucaparib Before More Data Are Collected

Rucaparib is a monotherapy treatment for adults with mutations in breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2) and recurrent mCRPC. Though it demonstrated a respectable response rate of 40%, the TRITON2 trial was a single-arm study based on objective response rates, which is not generally a surrogate for overall survival and not an endpoint on which FDA approval is normally based. Approving the drug now would mean the FDA is establishing a new definition for drug discovery and registrational studies.

Market Analysis

While FDA approval is a necessary step in a drug’s success, it is not sufficient. Some combination of healthcare stakeholder attitudes toward the use of a drug also affects the drug’s uptake and ultimately contributes to the drug’s market success.

Will PARP Inhibitors Prove Valuable in the Treatment of Prostate Cancer?

Should the FDA approve PARP inhibitors, their actual level of clinical use against prostate cancer depends on several factors, the most important of which relate to patient outcomes and patient preferences.

Patients May View PARP Inhibitors as a Favorable Alternative to Chemotherapy

In this era of precision medicine, patient preferences are integral. Chemotherapy can carry a negative connotation among patients, an attitude that may drive decision making around the course of treatment. Though clinicians may feel that back-to-back NHAs will not be as effective as chemotherapy, patients are often more comfortable with any therapy that is not chemotherapy. This resistance to chemotherapy could indirectly bolster the market for PARP inhibitors.

But Many Interested Patients Will Not Qualify for PARP Inhibitors

Though prostate cancer patients may feel more comfortable with an alternative to chemotherapy, the market for PARP inhibitors is limited by the genetic basis of the indications, which will result in only about a quarter of those who qualify via screening for the drug.

Not everyone will be screened, so PARP inhibitors will likely be employed in fewer than 25% of mCRPC cases. However, because these drugs are not yet approved, we don’t know the details of how screening logistics will affect the likelihood that physicians suggest this approach and patients want to pursue it. Those lessons will help clarify the level at which approved PARP inhibitors are clinically utilized.

Future Directions

PARP inhibitors will likely soon enter the prostate cancer therapy space, but uptake may initially be modest because of other available therapeutic options. As clinicians, we don’t interpret drug approval as an indication that a drug is necessarily better for our patients than the alternatives.

Despite the promising effects of olaparib in the PROfound trial, it is disheartening to see that the time to radiographic progression is only 7.5 months. For a precision medicine approach that involves choosing the drug, screening the patients, and then providing the treatment, it would be much more encouraging to see data that suggest that after undergoing this process, progression will not occur for a more extended time period.

Similarly with rucaparib, the current data do not meet the threshold for which we would expect the FDA to approve the drug. However, with the next batch of data coming from TRITON3, there will likely be evidence that rucaparib extends the radiographic progression-free survival (rPFS) and overall survival.

The data from other PARP inhibitor trials have not yet provided any insights beyond those revealed through the PROfound and TRITON studies. For instance, the GALAHAD study with Janssen’s niraparib, also known as Zejula, is producing results that largely mimic those seen with rucaparib, with patients with BRCA1 and BRCA2 mutations responding well, but those with ATM not responding as well as we had expected. Talazoparib, tested as Pfizer’s Talzenna in the TALAPRO-1 trial, is ongoing but appears also to be providing data consistent with what was observed in TRITON2.

As evidence builds for the value of individual PARP inhibitor drugs, these drugs may get utilized at higher rates than what will be seen in the early months following approval. We should also keep an eye on promising data around combining PARP inhibitor drugs with NHAs like abiraterone. These combination therapies may negate the need for genomic testing and thereby avoid practical hurdles related to providing patients access to the PARP inhibitor molecules. Even a subtle advantage like this could be what ultimately determines which drug is most successful from a market perspective.

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About Dr. Stephen Freedland

Dr. Stephen Freedland, Professor of Surgery and Associate Director, Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai, has been a professor and active practitioner in the field of urological oncology for the past 14 years. Prior to his current role, Dr. Freedland served on the faculty at Duke University. He also practices part time within the Veterans Health Administration system. Dr. Freedland has authored over 500 articles in the field of prostate cancer and typically treats approximately 50 patients per month. He has served on multiple American Urological Association and American Society of Clinical Oncology Guideline panels for prostate cancer in the past five years and he is leading several investigator initiated clinical trials looking at the role of diet in prostate cancer.

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This article is adapted from the January 27, 2020, GLG teleconference “PARP Inhibition in Prostate Cancer.” If you would like access to this teleconference or would like to speak with Dr. Freedland is or any of our more than 700,000 experts, contact us.