First-Line Combination Treatment with PARP and Androgen Receptor-Signaling Inhibitors in HRR-Deficient mCRPC: Applying Clinical Study Findings to Clinical Practice in the United States - Beyond the Abstract
October 9, 2024
While most patients with prostate cancer are diagnosed with localized disease, a subset will develop metastatic disease, and subsequently castration-resistant prostate cancer (mCRPC), which remains incurable. Additionally, an increasing number of patients will present with de novo metastatic prostate cancer, known as metastatic castration-sensitive prostate cancer (mCSPC), and may progress to mCRPC. In the mCSPC setting, treatment intensification of androgen deprivation therapy (ADT) with androgen receptor (AR) pathway inhibitors (ARPIs; alternatively called androgen receptor signaling inhibitors or ARSIs), with or without docetaxel, has improved overall survival versus ADT alone. However, real-world evidence indicates that many men with mCSPC do not receive such treatment intensification.
Biographies:
Rana McKay, MD, Medical Oncologist, Associate Professor of Medicine, UC San Diego School of Medicine, San Diego, CA
Biographies:
Rana McKay, MD, Medical Oncologist, Associate Professor of Medicine, UC San Diego School of Medicine, San Diego, CA
Related Content:
First-Line Combination Treatment with PARP and Androgen Receptor-Signaling Inhibitors in HRR-Deficient mCRPC: Applying Clinical Study Findings to Clinical Practice in the United States - Beyond the Abstract
First-Line Combination Treatment with PARP and Androgen Receptor-Signaling Inhibitors in HRR-Deficient mCRPC: Applying Clinical Study Findings to Clinical Practice in the United States
First-Line Combination Treatment with PARP and Androgen Receptor-Signaling Inhibitors in HRR-Deficient mCRPC: Applying Clinical Study Findings to Clinical Practice in the United States - Beyond the Abstract
First-Line Combination Treatment with PARP and Androgen Receptor-Signaling Inhibitors in HRR-Deficient mCRPC: Applying Clinical Study Findings to Clinical Practice in the United States
Read the Full Video Transcript
Rana McKay: Hello, I'm Rana McKay. I'm a medical oncologist at the University of California San Diego. This presentation is a beyond-the-abstract commentary about our recent publication and the cancer treatment reviews.
The paper discusses the approved PARP inhibitors plus androgen receptor pathway inhibitors, or ARPIs, for patients with metastatic castration-resistant prostate cancer within the context of the US treatment landscape.
Included in this review is an overview of considerations for these combination treatments in clinical practice, a discussion of the importance of testing for homologous recombination repair, or HRR gene alterations, as well as the benefits of treatment intensification for patients with mCRPC.
Alterations in HRR genes are found in approximately one-quarter of patients with advanced prostate cancer. Such alterations may signal a sensitivity to treatment with PARP inhibitors. Indeed, four PARP inhibitors have demonstrated antitumor activity as monotherapy in patients with mCRPC, of which olaparib and rucaparib have been approved as monotherapy by the FDA.
Three recent phase-3 clinical trials, TALAPRO-2, PROpel and MAGNITUDE, evaluated the combination of a PARP inhibitor with an ARPI, to lead to the approval in the US for talazoparib plus enzalutamide for patients with any HRR gene alterations. And for olaparib and niraparib, each combined with abiraterone for patients with BRCA alterations.
Preclinical and clinical evidence suggests four mechanisms that may underlie combined activity of PARP inhibitors in combination with an ARPI. First, PARP inhibitors may attenuate resistance to ARPIs, which are alternatively called ARSIs in this slide. Second, inhibition of the androgen receptor, the AR, for short, may upregulate PARP, as well as other components of machinery of HRR, and induce sensitivity to PARP inhibitors. Third, PARP inhibition may decrease the activity of the androgen receptor, downregulating AR genes. And fourth, ARPIs may downregulate HRR genes, leading to BRCAness.
In TALAPRO-2, patients were prospectively tested for HRR gene alterations using a 12-gene panel and enrolled in two independently-powered cohorts, an all-cover cohort and a combined HRR-deficient cohort. In PROpel, the patients were randomized to a treatment group, then retrospectively assessed for HRR gene alterations using a 14-gene panel. And finally, in MAGNITUDE, patients were prospectively tested HR gene alterations using a nine-gene panel, then separated into an HRR-deficient cohort and a non-HRR-deficient cohort.
Results from TALAPRO-2 demonstrated benefit in radiographic progression-free survival, known as rPFS, for short, in both the all-comer population and in the combined HRR-deficient population for patients who received talazoparib plus enzalutamide. There was also a benefit demonstrated in the non-HRR-deficient population who received this combination.
PROpel also demonstrated benefit in rPFS regardless of HRR gene alteration status, and in HRR-altered and non-altered for patients who received olaparib plus abiraterone. In the MAGNITUDE trial, futility was declared for the non-HRR-deficient cohort, but there was a benefit in rPFS in the HRR-deficient cohort for patients who received niraparib plus abiraterone.
When it comes to practical considerations, genetic testing has become an indispensable tool in the management of prostate cancer, as recommended by the NCCN and the AUA guidelines, and is key in informing treatment options and familial risk. While tumor tissue testing is the gold standard for DNA testing, it may not always be possible to obtain a high-quality sample. And ctDNA testing can be a viable alternative. False negatives may result from the use of old tissue samples in which the DNA has degraded, or samples with a low quantity of DNA. Therefore, testing for HR deficiency at the time of initial diagnosis of advanced prostate cancer without waiting for the onset of mCRPC is key.
Although the treatment landscape for mCSPC is evolving, most patients in TALAPRO-2, PROpel, and MAGNITUDE had only received androgen deprivation therapy for mCSPC. Based on real-world studies in the US, up to half of patients do not receive any life-prolonging therapy after their first-line therapy, supporting upfront intensification. Results from these three combination studies suggest that a subsequent ARPI plus PARP inhibitor may benefit patients who have received a prior ARPI.
Two additional studies, BRCAAWAY and PROfound, have investigated sequencing therapies in mCRPC. The BRCAAWAY study demonstrated that treating with a PARP inhibitor plus an ARPI was more effective than either monotherapy sequencing. And the PROfound study found that following first-line ARPI, sequencing olaparib improved medium rPFS compared with enzalutamide or abiraterone.
Adverse events were common across TALAPRO-2, PROpel, and MAGNITUDE, particularly anemia, and were commonly managed by supportive care and dose modifications. Despite the incidences of dose interruptions and discontinuations, the rate of permanent discontinuation of the PARP inhibitor was between 11 and 19% across the studies.
So, in conclusion, there is a compelling rationale to use a PARP inhibitor plus an ARPI as upfront therapy, and the combination is a promising new standard of care option in the frontline mCRPC setting. Recent FDA approvals of talazoparib plus enzalutamide and olaparib or niraparib plus abiraterone mean that screening for HMR alterations is important for all patients with advanced prostate cancer, to identify those who may benefit from these treatments.
This work was sponsored by Pfizer, and medical writing support for this video was provided by Annette Smith on behalf of CMC Affinity, a division of IPG Health Medical Communications, and was funded by Pfizer.
Rana McKay: Hello, I'm Rana McKay. I'm a medical oncologist at the University of California San Diego. This presentation is a beyond-the-abstract commentary about our recent publication and the cancer treatment reviews.
The paper discusses the approved PARP inhibitors plus androgen receptor pathway inhibitors, or ARPIs, for patients with metastatic castration-resistant prostate cancer within the context of the US treatment landscape.
Included in this review is an overview of considerations for these combination treatments in clinical practice, a discussion of the importance of testing for homologous recombination repair, or HRR gene alterations, as well as the benefits of treatment intensification for patients with mCRPC.
Alterations in HRR genes are found in approximately one-quarter of patients with advanced prostate cancer. Such alterations may signal a sensitivity to treatment with PARP inhibitors. Indeed, four PARP inhibitors have demonstrated antitumor activity as monotherapy in patients with mCRPC, of which olaparib and rucaparib have been approved as monotherapy by the FDA.
Three recent phase-3 clinical trials, TALAPRO-2, PROpel and MAGNITUDE, evaluated the combination of a PARP inhibitor with an ARPI, to lead to the approval in the US for talazoparib plus enzalutamide for patients with any HRR gene alterations. And for olaparib and niraparib, each combined with abiraterone for patients with BRCA alterations.
Preclinical and clinical evidence suggests four mechanisms that may underlie combined activity of PARP inhibitors in combination with an ARPI. First, PARP inhibitors may attenuate resistance to ARPIs, which are alternatively called ARSIs in this slide. Second, inhibition of the androgen receptor, the AR, for short, may upregulate PARP, as well as other components of machinery of HRR, and induce sensitivity to PARP inhibitors. Third, PARP inhibition may decrease the activity of the androgen receptor, downregulating AR genes. And fourth, ARPIs may downregulate HRR genes, leading to BRCAness.
In TALAPRO-2, patients were prospectively tested for HRR gene alterations using a 12-gene panel and enrolled in two independently-powered cohorts, an all-cover cohort and a combined HRR-deficient cohort. In PROpel, the patients were randomized to a treatment group, then retrospectively assessed for HRR gene alterations using a 14-gene panel. And finally, in MAGNITUDE, patients were prospectively tested HR gene alterations using a nine-gene panel, then separated into an HRR-deficient cohort and a non-HRR-deficient cohort.
Results from TALAPRO-2 demonstrated benefit in radiographic progression-free survival, known as rPFS, for short, in both the all-comer population and in the combined HRR-deficient population for patients who received talazoparib plus enzalutamide. There was also a benefit demonstrated in the non-HRR-deficient population who received this combination.
PROpel also demonstrated benefit in rPFS regardless of HRR gene alteration status, and in HRR-altered and non-altered for patients who received olaparib plus abiraterone. In the MAGNITUDE trial, futility was declared for the non-HRR-deficient cohort, but there was a benefit in rPFS in the HRR-deficient cohort for patients who received niraparib plus abiraterone.
When it comes to practical considerations, genetic testing has become an indispensable tool in the management of prostate cancer, as recommended by the NCCN and the AUA guidelines, and is key in informing treatment options and familial risk. While tumor tissue testing is the gold standard for DNA testing, it may not always be possible to obtain a high-quality sample. And ctDNA testing can be a viable alternative. False negatives may result from the use of old tissue samples in which the DNA has degraded, or samples with a low quantity of DNA. Therefore, testing for HR deficiency at the time of initial diagnosis of advanced prostate cancer without waiting for the onset of mCRPC is key.
Although the treatment landscape for mCSPC is evolving, most patients in TALAPRO-2, PROpel, and MAGNITUDE had only received androgen deprivation therapy for mCSPC. Based on real-world studies in the US, up to half of patients do not receive any life-prolonging therapy after their first-line therapy, supporting upfront intensification. Results from these three combination studies suggest that a subsequent ARPI plus PARP inhibitor may benefit patients who have received a prior ARPI.
Two additional studies, BRCAAWAY and PROfound, have investigated sequencing therapies in mCRPC. The BRCAAWAY study demonstrated that treating with a PARP inhibitor plus an ARPI was more effective than either monotherapy sequencing. And the PROfound study found that following first-line ARPI, sequencing olaparib improved medium rPFS compared with enzalutamide or abiraterone.
Adverse events were common across TALAPRO-2, PROpel, and MAGNITUDE, particularly anemia, and were commonly managed by supportive care and dose modifications. Despite the incidences of dose interruptions and discontinuations, the rate of permanent discontinuation of the PARP inhibitor was between 11 and 19% across the studies.
So, in conclusion, there is a compelling rationale to use a PARP inhibitor plus an ARPI as upfront therapy, and the combination is a promising new standard of care option in the frontline mCRPC setting. Recent FDA approvals of talazoparib plus enzalutamide and olaparib or niraparib plus abiraterone mean that screening for HMR alterations is important for all patients with advanced prostate cancer, to identify those who may benefit from these treatments.
This work was sponsored by Pfizer, and medical writing support for this video was provided by Annette Smith on behalf of CMC Affinity, a division of IPG Health Medical Communications, and was funded by Pfizer.