PROfound Data Could Lead to First PARP Inhibitor Approval in mCRPC

Alan H. Bryce, MD

On the heels of the phase III PROfound trial data, Alan H. Bryce, MD, explained that interest continues to pique regarding PARP inhibitors for men with metastatic castration-resistant prostate cancer (mCRPC).

“Happily, the pace of change has not slowed down in metastatic disease," said Bryce. “Certainly, based on the [PROfound trial] data, we are hopeful that olaparib (Lynparza) will receive FDA approval in the United States in the not-too-distant future.”

In PROfound, patients with heavily pretreated mCRPC were enrolled in 1 of 2 cohorts. Cohort A comprised patients with alterations in BRCA1/2 or ATM, while cohort B included those with an alteration in BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, or RAD54L. Within each cohort, patients were randomized in a 2:1 ratio to olaparib or physician's choice of abiraterone acetate (Zytiga) plus prednisone or enzalutamide (Xtandi).

Results showed that for patients in cohort A, the 12-month radiographic progression-free survival (rPFS) rate with olaparib was 40% versus 11% with abiraterone or enzalutamide. Median rPFS was 7.39 months compared to 3.55 months, respectively (HR, 0.34; 95% CI, 0.25-0.47; P <.0001). Though an overall survival (OS) improvement was noted, it was not statistically significant due to an 80.6% crossover rate. In cohort B, the benefit for olaparib was less versus the control arm, as the hazard ratio for rPFS by blinded review was 0.88 (95% CI, 0.58-1.36).

Though chemotherapy remains a staple treatment strategy in this setting, other immunotherapeutic agents and radiopharmaceuticals like lutetium-177 prostate-specific membrane antigen (PSMA; Lu-PSMA)-617 are being explored.

“There are a lot of clinical trials looking at immunotherapy in prostate cancer,” explained Bryce. “For patients who are frustrated by the lack of [immunotherapy] availability, we are working on it and haven't given up. Personally, I believe there will be immunotherapy options in prostate cancer, we just have to crack the code.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Genitourinary Cancers, Bryce, an assistant professor of medicine, and chair of the Division of Hematology/Oncology, Department of Internal Medicine, at Mayo Clinic, discussed encouraging updates and emerging strategies in metastatic prostate cancer treatment.

OncLive: What is the state of metastatic prostate cancer treatment?

Bryce: Right now, we have seen the first of the phase III studies of [PARP inhibitors in prostate cancer] read out at the 2019 ESMO Congress. Olaparib was shown to be effective in HRR gene-altered prostate cancer with improvements in rPFS and OS when randomized against an androgen receptor (AR) inhibitor.

The study of Lu-PSMA-617 completed accrual. Hopefully by late 2020 we will see some outcomes in terms of OS, as early data from [investigators in] Australia and Germany were promising.

Other PARP inhibitors in the pipeline, including rucaparib (Rubraca) and niraparib (Zejula), are continuing to accrue. I am hopeful we will see a space with multiple PARP inhibitors available, with some distinguishing characteristics between them.

Other radiopharmaceuticals are certainly being developed after Lu-PSMA-617, including actinium and thorium, as well as complex isotopes with PSMA as the delivery vehicle.

Immunotherapy is starting to see more activity, and bispecific monoclonal antibodies are in development and certainly are interesting.

Finally, we have had definitive, hopefully debate-settling proof of cabazitaxel (Jevtana) versus the AR inhibitors. From a scientific perspective, it’s not surprising that cabazitaxel is better than using a second AR inhibitor, either abiraterone or enzalutamide, after using another AR inhibitor plus docetaxel [upfront].

In terms of providing definitive data to give people confidence, we have settled that point and now people can look at that study and have confidence that chemotherapy is the answer. There is a lot of cross-resistance between the oral drugs. Once one is used, you don't get a lot of mileage out of a second [AR inhibitor].

What is the importance of the PROfound trial results?

In prostate cancer, we have known that BRCA mutations are common; it surprised many people how common this truly is. We argued for years that we should introduce PARP inhibitors into this space.

It was first demonstrated in the TOPARP study that there was efficacy with using olaparib, which launched the era of PARP inhibitor trials in prostate cancer.

The first randomized phase III trial to read out was the PROfound study of olaparib versus abiraterone or enzalutamide in patients who have had at least 1 of the prior drugs; also, almost two-thirds of patients had prior docetaxel.

In the BRCA1/2-mutant patients, there is a clear advantage to using olaparib both in terms of rPFS and in OS—despite the fact that crossover was allowed. This makes a point for getting the drug in early as it still maintains a survival benefit, rather than delaying it or using it later. The results were less impressive with ATM alterations and other less common mutations.

What is the advantage of using radiopharmaceuticals?

Currently, we have radium-223 dichloride (Xofigo) [as an available radiopharmaceutical in prostate cancer]. It's a good drug with a proven survival advantage in minimally symptomatic patients who have metastases limited to the bone.

This is a significant patient population, as bone is a “favorite” site for prostate cancer metastases. When you look at the periodic table and think about the inorganic chemistry of radium, radium tends to be absorbed by the body similarly to how calcium is—that is to say, concentrated in the bone.

Radium-223 takes advantage of that property and radioactively emits an α-particle. This means the radiation becomes concentrated and does not travel far before dropping off. In patients with bone-limited metastatic disease, there is both a palliative benefit in terms of relief of pain, and a survival benefit in terms of long-term outcomes.

Could you speak to the potential of LuPSMA?

The next generation of radiopharmaceuticals [is coming]. A study with lutetium-177, which is attached to PSMA, has recently completed accrual. In prostate cancer, PSMA receptors on the surface of cancer cells are overexpressed relative to normal tissue. Most of the expression in non-prostate tissue is in salivary and lacrimal glands.

When you combine lutetium-177 with PSMA, the radioactive isotope is selectively delivered mostly to prostate cancer cells within the body. Unlike radium-223, which relies on the inorganic chemistry for delivery to the bone, PSMA-targeting means it is equally delivered in bone, soft tissue, or any location of metastasis within the body. PSMA is ultimately used as the targeting vehicle to get the radiation delivered to the prostate cancer cell and then the lutetium radiation decays and releases in proximity to the cancer cell.

This was originally developed in Germany followed by testing in Australia. Early results in limited, single-arm studies were very promising. The phase III study has been accrued in the United States and overseas. In 2020, we are hopeful we will see some output from that.

What are your sentiments regarding immunotherapy?

In prostate cancer so far, we have not cracked the code of how to make checkpoint inhibitors work. Multiple studies have happened but they have low response rates, generally in the single-digit range. In highly selected patient populations, we start to see double-digit response rates, but overall, they are poor response rates compared with what you see in tumors where checkpoint inhibitors are approved for use, such as melanoma, bladder cancer, and renal cell carcinoma.

In prostate cancer, there is clearly a population of patients who benefit [from checkpoint inhibitors]. The challenge we have is identifying who those patients are. What is the selection criteria? Are checkpoint inhibitors the right answer or is there another immunotherapeutic approach that is required?

There is some suggestion that high microsatellite instability becomes a useful marker in prostate cancer; however, that is identified in 2% to 3% of patients with prostate cancer.

We have recently participated in data presented at the 2019 ESMO Congress showing that CDK12 is perhaps a predictor of response to checkpoint inhibition in prostate cancer. When CDK12 is somatically mutated in a prostate cancer cell, it leads to genomic instability and a high rate of large tandem exon duplications, as well as chromosomal rearrangements.

Tumor mutational burden (TMB) is exciting in a lot of other cancers. In prostate cancer, the mediate TMB is on the order of 2 where generally, TMB-high is considered 10 mutations/megabase. Even the 90th percentile of TMB in prostate cancer is between 4 or 5; therefore, prostate cancer does not get [statistically] TMB-high. We are recognizing that TMB is simply a surrogate for neoantigens.

If that is the case, perhaps CDK12 will be a marker. There are other immunotherapeutic strategies we need to look at, whether those are bispecific antibodies or CAR T-cell products. There are other ways to generate immune responses with drugs that generate immunogenic cell death.

In the metastatic hormone-sensitive prostate cancer (mHSPC) space, what data have been reported?

This continues to be an important space. In the last 6 months, we have seen 2 new studies— TITAN and ENZAMET—read out in this space.

Up until this point, abiraterone and docetaxel were the 2 drugs proven to be efficacious and extend OS when added to androgen-deprivation therapy in mHSPC. Now, we can add enzalutamide and apalutamide (Erleada) to that list. Both studies looked at patients with mHSPC, but with slightly different entry criteria and, therefore, slightly different populations.

It is a challenge to interpret these various studies, including TITAN, ENZAMET, CHARTED, STAMPEDE, and ARCHES. These studies had slightly different patient mixes and entry criteria.

An important finding out of ENZAMET and TITAN is that the addition of an oral AR inhibitor in patients who already received docetaxel did not add any additional benefit. Docetaxel, abiraterone, enzalutamide, and apalutamide all work in this setting; however, should you give chemotherapy or an oral hormone-targeting drug?

We don't have a good way to know who is going to benefit more from which drug. The reflex—and we see this in clinical practice—is to say, “Let's do all of the above. Let's give chemotherapy first, and then follow-up with one of the oral agents.”

At this point, we can definitively say that there is no benefit to doing [all of the above]. Before people start pushing back, given the expense of the drugs and potential toxicity, the onus is on the community to prove that adding the second drug works.

At this point, you pick one. Hopefully, we will get to an era where we are able to select patients in a rational method, such as through genomic selectors or clinical criteria, but we are not there yet. For now, don't accumulate extra toxicity by piling on multiple drugs.

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. Ann Oncol. 2019;30(suppl_5)mdz394.039. doi: 10.1093/annonc/mdz394.039.