Steven Christopher Smith, MD, PhD:
Now that we have reviewed the rationale and considerations when testing for HRR mutations, I would like to discuss a case application with Dr Beltran.

Our first case concerns a White man who is now 64 years old. He was diagnosed 8 years ago with prostate cancer, initially with a Grade Group 3 (4 + 3 = 7) at biopsy. This was upgraded to a Grade Group 4 (5 + 3 = 8) at prostatectomy, which showed positive margins along with intraductal and cribriform patterns.

He underwent early salvage radiotherapy and short‑term ADT. From that point until the present, he experienced rising PSA with intermittent ADT. This period is nebulous because the patient had limited access to insurance and care, and he was incarcerated.

Unfortunately, upon reestablishing care, bone metastases were detected. The patient initiated a combination of abiraterone and prednisone, which provided good disease control until just recently, when he experienced progressive metastases and epidural mass with spinal cord compression. He then underwent a procedure to mitigate the significant risk of paralysis, which afforded the opportunity for somatic sampling and molecular profiling.

Steven Christopher Smith, MD, PhD:
Shown here is a representative section of a slide from the patient. One important point is that the sample shows conventional high-grade prostatic adenocarcinoma. There was no evidence of neuroendocrine transformation.

Second, a portion of bone is present here. This raises a key consideration that we did not mention earlier. With bone samples, it is very important to use EDTA decalcification rather than acid decalcification to preserve nucleic acids for molecular profiling.

For this patient, we were able to detect a deleterious PALB2 variant using comprehensive genomic profiling.

Dr Beltran, what is your perspective on this case?

Himisha Beltran, MD:
This is a really interesting case that illustrates the long natural history from high‑risk prostate cancer to metastatic disease that progresses after primary ADT to CRPC, followed by progression on abiraterone and prednisone. This is a point where we want to know the patient’s genomic status, and having a contemporary tumor biopsy is ideal.

It is not always feasible to do bone biopsies, which, as you mentioned, require special considerations by interventional radiology and pathology. This is a situation where we want to communicate with the surgeon and the pathologist that genomic testing is requested in addition to standard pathologic assessment of histology and other features.

Dr Smith, could you elaborate on some of the challenges of handling bone biopsies when doing genomic testing?

Steven Christopher Smith, MD, PhD:
Yes. This is an important issue where a conversation beforehand with the lab would be useful. As I mentioned, we use EDTA to gently decalcify osseous samples because this agent still affords tissue fixation while preserving nucleic acids for potential downstream molecular testing. Pathology labs are increasingly using EDTA as medical oncologists request more molecular testing of bone metastases.

Dr Beltran, I know you will be speaking shortly on treatment considerations for patients with HRR mutations. Could you briefly share your thoughts on treatment selection for this patient?

Himisha Beltran, MD:
As we will shortly discuss, there are numerous options for patients with metastatic CRPC. The important finding here is the PALB2 mutation, which is an HRR mutation that has been associated with PARP inhibitor sensitivity. This expands the patient’s options beyond other standard treatments, such as docetaxel, to now include PARP inhibitors. Whatever treatment is selected, we also would add a bone-targeted agent (denosumab or zoledronic acid) for this patient, who had a skeletal‑related event at CRPC.

Steven Christopher Smith, MD, PhD:
Yes. I am happy to share that the patient has had nice disease stabilization on the PARP inhibitor olaparib.

Himisha Beltran, MD:
Olaparib is 1 of 2 approved options for PARP inhibitor monotherapy in the treatment of metastatic CRPC. For our patient with metastatic CRPC harboring a pathogenic PALB2 mutation who had progression on prior ADT and an AR pathway inhibitor, we could consider olaparib, which is approved as monotherapy across 14 HRR mutations in this setting.¹⁷ By contrast, rucaparib is approved only for alterations in BRCA1 and BRCA2, with the current indication also requiring prior receipt of a taxane chemotherapy.¹⁸

For either agent, patients should continue on their ADT. We usually give PARP inhibitors until progression or unacceptable toxicity.

Steven Christopher Smith, MD, PhD:
Dr Beltran, the FDA approved companion diagnostics for identifying patients eligible for these agents. How does your practice approach testing?

Himisha Beltran, MD:
At my practice, we perform local Clinical Laboratory Improvement Amendments (CLIA)-based tumor testing to determine eligibility for PARP inhibitors. We do not find it necessary to send out for commercial testing. Testing through Foundation Medicine was used in most of the trials, though most CLIA-based genomic tests typically include the relevant genes.

Steven Christopher Smith, MD, PhD:
My institution also uses local testing, although when patients come to our center for second opinions we certainly review and use genomic testing reports performed at national reference labs previously ordered by outside providers, as well.

Himisha Beltran, MD:
Here are the trials that led to approval of olaparib and rucaparib as monotherapy in this setting. We will cover the key findings shortly, but it is helpful to first summarize the study designs.

The phase III PROfound trial enrolled a population previously treated with abiraterone or enzalutamide, with 395 to 46% also having received prior docetaxel.⁴⁴ Participants were randomized to receive olaparib or the other AR pathway inhibitor (ie, abiraterone-experienced patients switched to enzalutamide, and vice versa). All patients had to undergo prospective central testing and were eligible only if they had a mutation in 1 of 15 HRR genes.

PROfound participants were assigned to cohorts based on their HRR alteration: Cohort A had alterations in ATM, BRCA1, or BRCA2—the most common mutations—and Cohort B had alterations in 12 other HRR genes that are less frequent in prostate cancer. Ultimately, olaparib was approved for 14 of these HRR mutations, excluding only PPP2R2A.

The single-arm phase II TRITON2 trial led to accelerated approval of rucaparib (NCT02952534).^18,43,45,46 This trial recruited patients treated with a prior AR pathway inhibitor and taxane chemotherapy who had a mutation in 1 of 15 HRR genes. However, rucaparib was approved only for alterations in BRCA1 and BRCA2.

The phase III TRITON3 trial is intended to lead to full approval of rucaparib. This trial enrolled patients with a prior AR pathway inhibitor, although 21% to 23% also had prior docetaxel for hormone-sensitive disease (NCT02975934).⁴⁷ Participants were randomized to receive physician’s choice—either an AR pathway inhibitor or docetaxel—or rucaparib. This trial enrolled only patients with mutations in ATM, BRCA1, or BRCA2. It is important to note that although we have positive data from the phase III TRITON3 trial, rucaparib has the accelerated approval based only on the phase II TRITON2 trial.

Himisha Beltran, MD:
Shown here are the Kaplan-Meier curves from the PROfound trial for rPFS, the primary endpoint, and OS in cohort A with BRCA1, BRCA2, and ATM mutations.^44,48 Recall that this trial compared olaparib with switching the AR pathway inhibitor in patients previously treated with abiraterone or enzalutamide, and a substantial minority had prior docetaxel.

You can see there was significant rPFS benefit with olaparib, with an HR of 0.34 (95% CI: 0.25-0.47; P <.001). There was also a significant OS benefit with an HR of 0.69 (95% CI: 0.50-0.97; P = .02). These data show that switching the AR pathway inhibitor is not effective and is not a good decision for most patients.

The overall population, which included those in cohort B with rarer HRR mutations, also showed a significant rPFS benefit (HR: 0.49; 95% CI: 0.38-0.63; P <.001). An exploratory analysis suggested OS benefit in the overall population, excluding those with PPP2R2A.

Therefore, olaparib was approved for the overall population (except PPP2R2A). However, there were considerably fewer patients with the rarer HRR genes, so it is challenging to make definitive conclusions for those harboring rarer HRR mutations. That said, let’s look at data from subgroup analyses for these other mutations.

Himisha Beltran, MD:
Here you see subset analyses from PROfound, including across some of the other HRR genes.⁴⁴ Mutations in BRCA2, CDK12, and ATM were more common than mutations in other HRR genes.

Himisha Beltran, MD:
As you can see in this figure, the small subset of patients with PPP2R2A mutations did not benefit from olaparib.⁴⁹ Alterations in this gene are not believed to confer sensitivity to PARP inhibition.

Recall that the case we first discussed featured a patient with a PALB2 mutation. Very few patients on PROfound had a PALB2 mutation, although this swimmer’s plot suggests some possible benefit with olaparib in those harboring PALB2 mutations. We know now from the TRITON2 trial and other studies in breast cancer that PALB2 is a canonical HRR gene similar to BRCA2 and imparts sensitivity to PARP inhibition.^46,50 Although PALB2 mutations are quite rare, I would not want to miss this alteration in a patient, like our case patient, because I might consider them for a PARP inhibitor.

Himisha Beltran, MD:
Let’s move on to data for rucaparib, our other PARP inhibitor approved as monotherapy. These are the response data from the cohort with BRCA1/2 mutations from the single-arm phase II TRITON2 trial, which evaluated rucaparib in patients with metastatic CRPC and HRR mutations after 1-2 lines of AR pathway inhibition and 1 taxane.⁴³ The primary endpoint was the objective response rate.

As you can see in the table on the right, the objective response rate was 43.5%. Responses occurred in patients with either BRCA1 or BRCA2 mutations, regardless of whether these were germline or somatic.

These data led to the accelerated approval for rucaparib in this setting, restricted to patients with BRCA1 or BRCA2 mutations.

Himisha Beltran, MD:
Here is a breakdown of rucaparib activity gene by gene in TRITON2.⁴⁶ Four patients had a PALB2 mutation, and all had a partial response—highlighting again the potential sensitivity of PALB2 to PARP inhibition. By contrast, none of the patients with a mutation in ATM, CDK12, or CHEK2 had a radiographic response in this study.

These data emphasize that there are differences in PARP inhibitor monotherapy sensitivity between HRR genes. We need to take this into consideration when evaluating testing results and making treatment recommendations.

Himisha Beltran, MD:
The phase III TRITON3 trial compared rucaparib with physician’s choice of either an AR pathway inhibitor switch or docetaxel in patients who had received 1 prior AR pathway inhibitor and no prior chemotherapy for metastatic CRPC.⁴⁷ What was impressive about this study is that the physician’s choice included chemotherapy, as opposed to just a switch in AR pathway inhibitors. Recall that this trial enrolled patients with alterations in BRCA1, BRCA2, or ATM.

As you can see here, there was a significant rPFS benefit with rucaparib in the subpopulation with BRCA1/2 mutations (HR: 0.50; 95% CI: 0.36-0.69; P <.001). These results provide further evidence that patients with BRCA1/2 mutations are the most likely to respond to PARP inhibition.

As mentioned above, although the phase III TRITON3 trial showed significantly prolonged rPFS with rucaparib in metastatic CRPC before treatment with docetaxel and post docetaxel, the accelerated approval is currently still for metastatic CRPC post docetaxel.

Steven Christopher Smith, MD, PhD:
To set up our final section on PARP inhibitor combination regimens, I would like to discuss a second case with Dr Beltran. This case concerns a Black man who is now 57 years old; 6 years ago, he had a biopsy that showed Grade Group 5 (4 + 5 = 9) prostate cancer in 12 cores. This was high-stage, locally advanced disease—pT3b at prostatectomy with 2-mm positive margins at the base and intraductal and cribriform patterns.

The patient had early salvage radiotherapy followed by several years with a low PSA and a nadir of 0.3. However, follow-up was somewhat sporadic during the COVID-19 pandemic. When the patient reestablished care, he was asymptomatic, but his PSA had unfortunately climbed to 283 ng/mL. He was referred for a PSMA PET scan to restage disease status, which demonstrated innumerable bone and lymph node metastases.

This was still during the pandemic, and the patient decided to receive ADT alone. Just recently, he presented with progressive lymphadenopathy and rapid growth of a supraclavicular lymph node. You can see from the ultrasound image that this node was sampled.

Steven Christopher Smith, MD, PhD:
Given the explosive cancer growth, his care team wanted to confirm that the histology was still conventional high‑grade prostate adenocarcinoma. The left image shows the limited core sample taken from aspiration of the rapidly growing node. As shown in the middle image, the carcinoma was poorly differentiated but was confirmed to be conventional prostate cancer through use of the immunohistochemistry markers NKX3.1 and p501S, which support prostatic lineage. Importantly, the lack of cytologic features of high-grade neuroendocrine transformation is useful, as disease management would likely be different. Because we obtained only a very limited core biopsy sample, it was actually the smear sections from the aspiration that yielded tissue for testing, as shown in the right image.

At our institution, our next-generation sequencing panel of 150 genes is validated for aspirate smears and tissue. In this sample, we were able to identify a TMPRSS2:ERG fusion, which confirms the prostatic origin of the disease, always relevant with poorly differentiated disease. But, relevant to our discussion, the testing panel also identified a BRCA2 frameshift mutation.

Dr Beltran, what is your perspective on this second case?

Himisha Beltran, MD:
My first impression is that this case highlights some of the challenges in managing patients during the pandemic. Back when the patient presented with innumerable bone and lymph node metastases—consistent with high-volume metastatic HSPC—that is when we would recommend intensfied treatment with addition of an AR pathway inhibitor to ADT, and maybe even triplet therapy with ADT, an AR pathway inhibitor, and docetaxel. That does not always happen in the real world, however, particularly during the height of the pandemic. Despite the level 1 evidence to intensify therapy, we do see patients with metastatic CRPC who have not had an AR pathway inhibitor.

In this situation where the patient has rapidly progressing disease, you could go to chemotherapy for swift disease control. However, it is great that you were able to get all this information on histology and molecular profiling so quickly. In the setting of a loss of function mutation involving BRCA2, combining an AR pathway inhibitor and a PARP inhibitor would be a potentially effective strategy.

Steven Christopher Smith, MD, PhD:
Yes. The patient was started on talazoparib plus enzalutamide.

Himisha Beltran, MD:
That is quite reasonable for a patient in this situation. Although we have limited data, it is likely that early intensification by combining an AR pathway inhibitor and a PARP inhibitor is better than sequential AR pathway followed by PARP inhibitor therapy in a patient with a BRCA2 mutation (based on the BRCAAway trial, which we will discuss below).

Moving on, we will now discuss the key trials and data behind these combinations.

Himisha Beltran, MD:
Why combine an AR pathway inhibitor with a PARP inhibitor in prostate cancer? Preclinical models suggest an interplay between PARP and AR signaling.⁵² For example, AR exerts transcriptional control over PARP1 and a subset of HRR genes, and AR knockdown in vitro induces downregulation of these HRR genes. Furthermore, in mouse xenograft models, AR pathway inhibition acts synergistically with PARP inhibition to inhibit tumor growth.^53,54

Although we should note that other PARP inhibitor combination strategies are in preclinical and clinical development, currently the only drugs approved by the FDA in combination with PARP inhibitors for metastatic CRPC are AR pathway inhibitors.

Himisha Beltran, MD:
The PARP inhibitor plus AR pathway inhibitor combination regimens approved by the FDA are niraparib plus abiraterone, olaparib plus abiraterone, and talazoparib plus enzalutamide.^16,17,19 Please note that the approvals are different: BRCA1 and BRCA2 mutations are the only alterations approved for niraparib plus abiraterone and olaparib plus abiraterone, whereas talazoparib plus enzalutamide has a broader indication with more eligible HRR alterations.

Himisha Beltran, MD:
The table here summarizes the design of the phase III trials that led to these approvals. The trials were very different in design but asked a similar question: What is the role of combination therapy with a PARP inhibitor and AR pathway inhibitor in managing first-line metastatic CRPC?

The PROpel trial compared olaparib plus abiraterone with placebo plus abiraterone.^55,56 This trial enrolled all-comers and did not require prospective HRR testing, although the investigators did perform retrospective testing in >98% of patients. The reason for evaluating the combination in all-comers was that, based on preclinical evidence, the investigators hypothesized that patients would not need to have an HRR alteration because the AR pathway inhibitor would synergize with the PARP inhibitor.

Ultimately, olaparib plus abiraterone was approved for patients with BRCA1 and BRCA2 mutations, and we will discuss the data and reasons for that shortly.¹⁷

The MAGNITUDE trial did have prospective testing for HRR alterations using tissue and ctDNA.^57,58 The investigators assigned patients with HRR mutations to one cohort and those without HRR mutations to a second cohort. The HRR mutation–negative cohort was closed for futility.

Niraparib plus abiraterone was approved just for BRCA1 and BRCA2 mutations despite MAGNITUDE enrolling patients with other HRR genes.¹⁶

The TALAPRO‑2 trial also had prospective testing for HRR alterations, and the primary endpoint was in the all-comers intention-to-treat (ITT) population.²⁰ That being said, this trial looked at specific cohorts with and without HR deficiency. Talazoparib plus enzalutamide was approved for patients with HRR mutations, as we will discuss soon.¹⁹  

All of these trials used Foundation assays, along with other commercial and local assays, for their testing.

Himisha Beltran, MD:
These are the Kaplan-Meier curves of rPFS from the PROpel trial comparing olaparib plus abiraterone with placebo plus abiraterone.^55,56 The trial met its primary endpoint of rPFS in the all-comers ITT population, with an HR of 0.66 (95% CI: 0.54-0.81; P <.001). When you look at the BRCA-mutated subpopulation on the right, however, the rPFS benefit was more profound, with an HR of 0.23 (95% CI: 0.12-0.43). These findings indicate that the rPFS benefit in the all-comers population likely was driven by the patients with BRCA1/2 mutations.

Himisha Beltran, MD:
The final OS data for PROpel were published in 2023 and showed a significant OS benefit in the BRCA‑mutated subpopulation, with an HR of 0.29 (95% CI: 0.14-0.56).⁵⁶ There was no significant OS benefit in the all-comers ITT population.

The PROpel data led to the observation that the greatest benefit with a PARP inhibitor combination is in patients with a BRCA1/2 mutation. That is one of the reasons the FDA approved this combination in the BRCA1/2‑selected subgroup.

Himisha Beltran, MD:
Recall that the MAGNITUDE trial had 2 cohorts, with the HRR mutation–negative cohort being closed for futility.^57,59 When we look at the entire HRR mutation–positive cohort, we see an rPFS benefit, but this benefit was even more pronounced in those with a BRCA1/2 mutation (HR: 0.53; 95% CI: 0.36-0.79; P = .0014).

Himisha Beltran, MD:
No OS benefit was observed in the broader HRR mutation–positive cohort.^58,60 In the final analysis of OS for the BRCA1/2‑mutated cohort, there was numerical OS benefit with an HR of 0.78 (95% CI: 0.554-1.120; nominal P = .1828).

Because of the significant rPFS and numerical OS benefit in the BRCA1/2-mutated subgroup, niraparib plus abiraterone was approved just for those mutations.

Himisha Beltran, MD:
TALAPRO‑2 enrolled an all-comers cohort and a cohort of patients with a mutation in at least 1 of 12 HRR genes.^20,61 There was a significant rPFS benefit with talazoparib plus enzalutamide vs placebo plus enzalutamide in all-comers, with a stratified HR of 0.63 (95% CI: 0.51-0.78; P <.0001). The rPFS benefit was more apparent, as you might expect, in the cohort with HRR gene deficiency (stratified HR: 0.45; 95% CI: 0.33-0.61; P <.0001).

Himisha Beltran, MD:
When you look at the rPFS results gene by gene for a subset of those HRR genes, the subset with BRCA2 mutations tended to do the best, just as we might expect—but there were some surprising findings. For example, earlier data indicated that CDK12 was not particularly responsive to PARP inhibition, but when the investigators defined a CDK12 cluster, this subset had rPFS benefit.

Based on these subgroup analyses and the design of the study with an all-comers ITT population, talazoparib plus enzalutamide was approved for a broader range of HRR gene mutations.

Himisha Beltran, MD:
These are the OS data, which are still immature, for TALAPRO-2.⁶¹

Himisha Beltran, MD:
What is the optimal sequence of PARP inhibitor and AR pathway inhibitor therapy? How do we know that giving the recently approved combination regimens up front is better than administering the AR pathway inhibitor first and then giving the PARP inhibitor at progression, as we have been doing? None of the 3 registrational trials had a treatment arm consisting of a PARP inhibitor alone, so none could answer these important questions.

The small but important randomized phase II BRCAAway trial, which was presented at ASCO GU 2024, sought to answer these questions. BRCAAway randomized 61 patients with metastatic CRPC who had BRCA1, BRCA2, or ATM mutations to receive abiraterone alone, olaparib alone, or olaparib plus abiraterone. Crossover between the monotherapy arms was permitted at progression.⁶² Most patients (>75%) had BRCA1/2 mutations, so I would consider the findings mostly applicable to the BRCA1/2-mutated population.

Himisha Beltran, MD:
The upfront combination arm had a median rPFS of 39 months, much longer than the median rPFS of 8.4 months with abiraterone and 14 months with olaparib.⁶² Both response rates and PSA response rates were highest among patients receiving the upfront combination.

These findings, along with data from the other combination trials, support upfront use of combination therapy in a patient with a BRCA1/2 mutation. These encouraging data from BRCAAway also suggest that we should be combining, rather than sequencing, PARP inhibitors and AR pathway inhibitors. That being said, BRCAAway is a small study, and more robust data are needed.