Acting on Actionable Mutations in Metastatic Prostate Cancer

Abstract

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

Approximately a quarter of men with metastatic castration-resistant prostate cancer have genomic alterations within the homologous recombination repair pathway with poly (ADP-ribose) polymerase (PARP) inhibitors as corresponding treatment options. How to incorporate genomic information and associated therapeutic options into treatment decision making and sequencing of therapies in prostate cancer remains challenging. Men with BRCA2 alterations seem to derive the most benefit from PARP inhibitors, and although early treatment in combination with standard therapies has not yet shown an overall survival benefit, there may be other benefits to incorporating PARP inhibitors early for some men.

How to act on genomic information in prostate cancer, especially when to treat w/parp inhibitors.

CASE PRESENTATION

A 71-year-old man presents to the clinic for follow-up of metastatic prostate cancer. He was first diagnosed with localized disease at the age of 62 years. At the time of diagnosis, he had clinical stage T3N0 disease and an initial prostate-specific antigen (PSA) of 8.5 ng/mL. He underwent radical prostatectomy and had an undetectable postoperative PSA. Four years after diagnosis, he developed biochemical recurrence and underwent salvage radiation therapy. Three years later, he again had a rising PSA. Conventional computed tomography showed pathologically enlarged retroperitoneal and mediastinal lymph nodes. Technitium-99 bone scan showed six sites of metastases in the thoracic spine, pelvis, rib, and femur. Next-generation sequencing was performed on the tumor from his radical prostatectomy specimen, and a pathogenic frameshift mutation in BRCA2 was found. Germline genetic testing was negative. He was started on androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone agonist and six cycles of docetaxel and had a disease response for approximately 18 months before he developed PSA progression. Follow-up imaging now shows radiographic progression in the lymph nodes with two new bone lesions. In addition to his prostate cancer, he has obesity with a body mass index of 30 kg/m²; hypertension, currently managed with two antihypertensive medications; hyperlipidemia treated with a statin; and gastroesophageal reflux disease treated with a proton pump inhibitor. He is very active, works out four times a week, and continues to work part time. Family history is notable for localized prostate cancer in his father that was cured. To summarize, this is a 71-year-old man with somatic BRCA2-altered metastatic castration-resistant prostate cancer (mCRPC) that has progressed after first-line treatment with ADT and docetaxel. The question to decide is what treatment to choose next and when to incorporate poly (ADP-ribose) polymerase (PARP) inhibitors into his treatment regimen given the somatic BRCA2 alteration.

FINDING AN ACTIONABLE TARGET

The number of genetic alterations that are potentially actionable in prostate cancer continues to increase. It is estimated that 12% of men with metastatic prostate cancer will have inherited pathogenic mutations in the DNA repair pathway,¹ and nearly a quarter of men with mCRPC will have somatic mutations in DNA repair pathway genes, the most common being BRCA2.² Approximately 1%-2% of men with advanced prostate cancer will have microsatellite unstable tumors, approximately 3% will have CDK12 alterations, and fewer than 5% will have tumors with high tumor mutational burden (TMB).^3-5 This is important because there are now therapies specific to those cancers (Table 1). In addition to the US Food and Drug Administration (FDA)–approved therapies, there are even more clinical trials for men with specific genomic alterations. Because of this, all patients with metastatic prostate cancer should be offered germline genetic testing and somatic next-generation sequencing of their tumor, consistent with national guideline recommendations, performed when patients become eligible for testing on the basis of the stage of disease.¹³

TABLE 1.

Treatment Options on the Basis of Genomic Targets in Prostate Cancer Compared With Selected Patients in MAGNITUDE and PROPEL Trials

WHEN TO ACT?

Immunotherapy

When an actionable mutation is found, the next question becomes when to use targeted therapy. Patients with microsatellite instability high disease or with a TMB of at least 10 would be eligible to receive pembrolizumab, according to the FDA approval, after there are no satisfactory alternative treatments.^9,14 Estimates of disease response rates in retrospective reviews are around 50% with immunotherapy for men with MSI-high prostate cancer and less than that for TMB-high prostate cancer.^15,16 In practice, typically immunotherapy is offered to these patients after one to three lines of standard prostate cancer therapies. Although the incidence of these tumors is low, it is only possible to identify these patients with next-generation sequencing testing.

PARP Inhibitors

Olaparib was approved for use in men with homologous recombination repair (HRR) alterations (Table 1) who have progressive disease after treatment with abiraterone or enzalutamide on the basis of improved overall survival (OS) in the PROFOUND study.¹⁷ Rucaparib was approved for men with BRCA1 or BRCA2 mutations who have progressive disease after treatment with a taxane chemotherapy and abiraterone or enzalutamide on the basis of overall response rates and prolonged progression-free survival in the TRITON-2 study.⁷ The TRITON-3 study recently demonstrated that rucaparib improved radiographic progression-free survival (rPFS) for patients with BRCA mutations before chemotherapy as well.¹⁸

Three additional trials help to shed light on moving PARP inhibitors earlier in the disease course and in combination with androgen receptor axis targeting agents to improve clinical outcomes. The MAGNITUDE study by Chi et al¹⁰ compared abiraterone/prednisone and niraparib (dosed at 200 mg once daily, lower dose than the FDA-approved dose for other cancers) with abiraterone/prednisone and placebo. This phase III trial randomly assigned patients progressing on ADT alone or after ADT and docetaxel treatment for metastatic castration-naïve prostate cancer. Patients were prospectively assigned to either the HRR-positive or HRR-negative cohort on the basis of the presence of HRR mutations (Table 1). Twenty five percent of the prescreened population was positive for an HRR mutation, consistent with previous estimates of prevalence.² The primary end point was centrally reviewed rPFS. On the basis of an interim futility assessment, the HRR-negative cohort closed. The HRR-positive cohort met its primary end point, demonstrating an improvement in rPFS of 16.5 months in the combination treatment arm compared with 13.7 months rPFS in the control arm (P = .022). Important secondary end points, including time to chemotherapy and time to symptomatic progression, were also improved with the combination of abiraterone/prednisone and niraparib compared with abiraterone/prednisone and placebo.

The PROPEL trial tested abiraterone/prednisone and olaparib versus abiraterone/prednisone and placebo in a population of men unselected for HRR mutations in the first-line setting of mCRPC.¹¹ Patients were tested for the presence of HRR mutations but not prospectively assigned to cohorts on the basis of those results (Table 1). The primary end point was investigator-assessed imaging based progression-free survival. PROPEL met its primary end point of an improvement in rPFS for both the HRR-positive and HRR-negative subgroups. The TALAPRO-2 study tested enzalutamide and talazoparib versus enzalutamide and placebo in a population of men unselected for HRR mutations, being treated in the first-line setting for mCRPC.¹² Patients were prospectively tested and stratified by the presence of HRR mutations (Table). The primary end point was blinded independent review of rPFS. The initial results of this trial showed, similar to the PROPEL trial, an improvement in rPFS for the population overall and the HRR-positive and -negative subgroups, although a greater benefit was seen in the HRR-positive subgroup. OS data are immature. Because of the differences in the study design, treatment doses in combination versus monotherapy, and end point assessment between the three studies, it is unclear at this time how to reconcile the discordant results in the HRR-negative populations of these studies. Furthermore, because of the increase in toxicity and the lack of data on OS as of yet, for unselected or patients without HRR mutations, the early combination of abiraterone/prednisone or enzalutamide with a PARP inhibitor is premature to do in routine clinical practice. For patients with HRR mutations, the results of these trials show similar benefits of combining abiraterone/prednisone with a PARP inhibitor. It is important to note that these outcomes seem to be greatest in the BRCA1/2 subgroup of patients and less pronounced in the subpopulations of patients with other HRR mutations.

Should PARP inhibitors be used in sequence after abiraterone or enzalutamide and potentially chemotherapy as in PROFOUND and the TRITON studies? Alternatively, in parallel, as in MAGNITUDE, PROPEL, and TALAPRO-2? In the MAGNITUDE trial, there was no improvement in OS, although with too few events, it is too early to draw conclusions. We also do not know what percentage of men in the control group crossed over and went on to receive niraparib or another PARP inhibitor after treatment. The OS data from PROPEL and TALAPRO-2 are immature. These data are critical before considering this combination as standard of care for all patients with HRR mutations. Additional trials, such as the TALAPRO-3 trial (ClinicalTrials.gov identifier: NCT04821622) and AMPLITUDE trial (ClinicalTrials.gov identifier: NCT04497844), are testing the addition of a PARP inhibitor for men with HRR-positive disease in combination with treatment for metastatic castration-naïve prostate cancer, potentially moving these treatments even earlier.

Although there were no unexpected toxicities of the combination of niraparib and abiraterone/prednisone, the adverse events do deserve mention. The rate of grade 3 anemia was four times higher in the combination arm compared with the placebo arm (28% v 7%). Grade 3 and 4 thrombocytopenia and neutropenia were not common overall but more common in the combination group (6.6% v 2.4% and 6.6% and 1.4%, respectively). Hypertension, constipation, fatigue, and nausea were all more common in the combination group. The quality of life data suggests better outcomes in the placebo group during the first approximately 4 months of treatment but similarities between the groups over time. Additionally, 20% of patients had to decrease the dose of niraparib (compared with 3% of placebo), and 11% of patients had to discontinue niraparib compared with 5% of patients on placebo because of adverse events.

These trials explore first-line treatment for mCRPC after ADT alone, with less than a quarter of patients having received additional therapies in the castration-naïve setting. Although ADT alone has been the standard treatment for metastatic prostate cancer for decades, the consensus now based on multiple clinical trials is to add chemotherapy or an oral androgen receptor pathway inhibitor (ARPI), or both, to initial ADT treatment.¹⁹ In practice not all men will receive additional therapy, but the use of doublet and triplet therapies for the treatment of metastatic castration-naïve prostate cancer is likely to and should increase as the evidence in support of this approach accumulates.²⁰

Who is the right patient for combination PARP inhibitor with abiraterone/prednisone? The patient who was treated with ADT alone in the first-line setting or with six cycles of docetaxel (although the benefit seems to be less in subset analysis) and has an HRR mutation should be considered for this approach. For patients who receive an ARPI in the castration-naïve setting, I would not recommend combination PARP inhibitor and abiraterone/prednisone as these patients were not included in either PROPEL or MAGNITUDE trials. The factors that might consider one to treat with ADT alone in the first-line setting, such as significant comorbidities or poor performance status, are likely to make doublet therapy in the mCRPC setting equally challenging. Given the toxicity profile of the combination PARP/abiraterone, for those patients already experiencing potential toxicities, such as anemia, I also would not recommend combination therapy (Fig 1). For patients who want to avoid chemotherapy for as long as possible and are willing to accept the risk of more side effects with the combination, the combination could be offered.

FIG 1.

Treatment algorithm for patients with mCRPC and pathogenic alteration in HRR pathway gene. ^aMore likely for the subset of patients with excellent performance status, minimal comorbidities or toxicities from therapies or their disease, patients who wish to avoid chemotherapy for as long as possible but willing to accept potentially more toxicities in the short term, with HRR pathway gene most likely to have disease response. ^bIf previous chemotherapy. ADT, androgen deprivation therapy; ARPI, androgen receptor pathway inhibitor; HRR, homologous recombination repair; mCRPC, metastatic castration-resistant prostate cancer; PSMA, prostate-specific membrane antigen.

The specific gene alteration found in the HRR pathway will also be relevant to patient and treatment selection. Previous studies of PARP inhibitor efficacy has shown that patients with BRCA2 alterations have the best disease response to PARP inhibitors compared with those with other HRR mutations.^21-23 In the case above, our patient has a pathogenic BRCA2 mutation so would be the most likely to have disease response to treatment with the addition of a PARP inhibitor. There is not agreement on which genes should be included in the definition of HRR. Genes such as CDK12 and HDAC2 were added to the list of HRR-positive mutations in the MAGNITUDE trial but absent from other trials and approvals (Table 1). More research is needed to understand how individual mutated cancer types are likely to respond to PARP inhibitor treatment and the combination, but I would be less likely to offer the combination of PARP inhibitor with abiraterone/prednisone for patients with mutations less likely to have a disease response, such as ATM or CDK12 alterations. Clinical trials for patients with these and other mutations would be the preferred treatment option as therapies targeting these mutations are being developed.

SUMMARY

Germline and somatic next-generation sequencing is essential for patients with metastatic prostate cancer as an increasing number of FDA-approved therapies are moving into the clinic and an increasing number of clinical trials are rationally selecting patients on the basis of genetic alterations in their cancers. For men with actionable HRR pathway alterations, especially BRCA1 or BRCA2, who have an excellent performance status, minimal toxicity from treatment of their cancer, I would offer a PARP inhibitor in combination with abiraterone and prednisone if they were previously treated with ADT or ADT and docetaxel, as the abovementioned patient. In this case, after reviewing the risks and benefits, the patient was started on combination PARP inhibitor and abiraterone/prednisone as he desired, primarily avoiding chemotherapy for as long as possible. However, the patient is unlikely to receive ADT or ADT/docetaxel alone now for metastatic castration-naïve prostate cancer and more likely to have an ARPI added in the castration-naïve setting. In that case, a PARP inhibitor alone in the first-line mCRPC setting would be recommended (Fig 1).

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Acting on Actionable Mutations in Metastatic Prostate Cancer

The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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