18F-FDG PET and PET/CT in the Evaluation of Cancer Treatment Response

Prostate Cancer Treatment Challenge: Which Drugs To Use First

Over the past 14 years, clinicians have seen rapid growth in their therapeutic armamentarium to treat advanced prostate cancer. They can now choose among 4 novel second-generation hormone therapies (the androgen receptor pathway inhibitors [ARPIs] abiraterone, enzalutamide, apalutamide, and darolutamide), 2 chemotherapy agents (docetaxel and cabazitaxel), 2 radiopharmaceuticals (radium-223 and lutetium-177-PSMA-617), 4 PARP inhibitors (olaparib, rucaparib, niraparib, and talazoparib), and a vaccine (sipuleucel-T). These medications can delay disease progression and prolong life, but their optimal use—such as which drug or drug combinations should be used first to achieve the best outcomes from prostate cancer treatment—is still being worked out.

Nevertheless, standards of care, or at least consensus on the best approaches in various clinical scenarios, have evolved based on accumulating evidence of efficacy and safety, advances in imaging that allow for more accurate cancer staging (such as prostate-specific membrane antigen positron emission tomography [PSMA PET]), and the use of genomic and other biomarkers that predict prostate cancer aggressiveness. Among the overarching trends is earlier and earlier treatment intensification to forestall development of metastases and castration-resistant prostate cancer (CRPC).

Medical societies regularly update guidelines in response to the latest data. For example, American Urological Association guidelines recommend either enzalutamide, apalutamide, or darolutamide in addition to androgen deprivation therapy (ADT) for patients with nonmetastatic CRPC at high risk for metastases. American Society of Clinical Oncology guidelines recommend triplet therapy consisting of either darolutamide or abiraterone combined with docetaxel and ADT for patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Triplet therapy with docetaxel plus an ARPI and ADT has become a widely accepted first-line treatment for patients with high-volume synchronous mHSPC—especially for those with visceral metastases—and who can tolerate chemotherapy, said Andrew J. Armstrong, MD, ScM, professor of medicine, surgery, pharmacology, and cancer biology at Duke University in Durham, North Carolina, where he is Director of Research at the Duke Cancer Institute Center for Prostate and Urologic Cancers. Doublet therapy is recommended for patients with metachronous low-volume disease.

Trial data support ADT/ARPI doublet therapy and radiation to the primary tumor (and possibly metastasis-directed radiation) for patients with synchronous low-volume disease, Dr Armstrong said. Patients with metachronous high-volume disease, a rare subgroup, may benefit from triplet therapy in selected cases, he said.

Still, there is room for improvement. "In the end, we would all benefit from more precise biomarkers of docetaxel benefit in this setting … and trials testing the value of docetaxel over doublet ADT/ARPI therapy," he said.

Recent network meta-analyses of randomized controlled trials (RCTs) have attempted to interpret data across trials to arrive at which first-line therapy for mHSPC and metastatic castration-resistant prostate cancer (mCRPC) would produce the best outcomes. In a network meta-analysis that included 10 RCTs with 11,043 patients with mHSPC, investigators found that triplet therapies of darolutamide plus docetaxel and ADT and abiraterone plus docetaxel and ADT are significantly associated with 32% and 25% lower risks for death, respectively, compared with docetaxel plus ADT doublet therapy, but do not improve survival compared with ARPI doublet therapy.1

Among patients with high-volume disease, triplet therapy with abiraterone plus docetaxel and ADT may improve overall survival compared with docetaxel plus ADT, but not compared with doublet therapies of abiraterone plus ADT, enzalutamide plus ADT, and apalutamide plus ADT, according to findings published in 2023 in JAMA Oncology.1 For patients with low-volume disease, abiraterone plus docetaxel and ADT may not improve overall survival compared with apalutamide plus ADT, abiraterone plus ADT, and enzalutamide plus ADT, and docetaxel plus ADT.

In a separate network meta-analysis published in European Urology Oncology in 2022, which included 11 RCTs with 11,546 patients, investigators concluded that triplet therapy with docetaxel plus an ARPI and ADT had a 77% likelihood of being the best treatment approach for mHSPC compared with a 23% likelihood for doublet therapy with an ARPI plus ADT.2

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"While meta-analyses are usually very helpful, there are a lot of nuances that they don't grasp."

More recently, in a network meta-analysis of 10 RCTs published in 2024 in the Asian Journal of Andrology, investigators reported that triplet therapy with darolutamide plus docetaxel and ADT offered the best overall survival among patients with mHSPC, followed by a triplet of abiraterone plus docetaxel and ADT.3 The best regimens for improving progression-free survival were the triplet therapies abiraterone or enzalutamide in addition to docetaxel plus ADT and doublet therapies consisting of ARPIs, according to the investigators. The triplet of darolutamide plus docetaxel and ADT offered the best treatment for lowering the risk for development of castration-resistant disease and symptomatic skeletal events. "Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT," the authors concluded.

Also in 2024, investigators published findings from a network meta-analysis of 7 phase 3 and 4 RCTs with 6641 patients upon which they concluded that chemotherapy offers superior overall survival compared with abiraterone and enzalutamide as first-line treatment for metastatic castration-resistant prostate cancer (mCRPC), which they acknowledged is not consistent with AUA guidelines.4

Compared with placebo, docetaxel, cabazitaxel 20 mg/m2, and cabazitaxel 25 mg/m2 significantly decreased the risk for death by 47%, 47%, and 48%, respectively, the investigators reported in Frontiers in Oncology. In contrast, abiraterone and enzalutamide significantly decreased death risk by 19% and 30%, respectively.

"Our comprehensive analysis revealed that chemotherapy, specifically docetaxel and cabazitaxel, demonstrated superior efficacy and safety compared to second-generation anti-hormonal therapies, including abiraterone, enzalutamide, and apalutamide, in the first-line management of mCRPC," corresponding author Yinfeng Ma, MD, of The Second Affiliated Hospital of Zhejiang Chinese Medicine University in Zhejiang, and colleagues wrote. After weighing the safety and efficacy data, the investigators recommended that cabazitaxel 20 mg/m2 plus prednisone should be the preferred therapy for first-line treatment, followed by docetaxel plus prednisone.

Prostate cancer specialists advise caution in their interpretation of network meta-analyses. Although they can provide useful information, meta-analyses "are not meant to replace the need for randomized phase 3 trials but can look at key questions across trials to infer ranking and superiority of types of therapeutic approaches grounded against a common control group," Dr Armstrong said.

The meta-analyses of mHSPC trials "all basically confirm concepts that are already well appreciated from the individual analyses of the key phase 3 trials in the mHSPC setting," he said.

"While meta-analyses are usually very helpful, there are a lot of nuances that they don't grasp," said Stephen J. Freedland, MD, Director of the Center for Integrated Research in Cancer and Lifestyle and Associate Director of Cedars-Sinai Cancer at Cedars-Sinai in Los Angeles, California.

With regard to the meta-analysis of mHSPC trials published in the Asian Journal of Andrology, Dr Freedland pointed out that with triplet therapies of chemotherapy combined with ADT and ARPI have only been compared with ADT plus chemotherapy doublet therapy. Consequently, it is unknown whether these triplet regimens are better than doublets of ADT plus an ARPI. In addition, in the CHAARTED trial, a doublet of ADT plus chemotherapy only showed benefit for patients with high-volume disease. "Thus, a blanket recommendation of triplet [therapy] for everyone is not supported by the literature, despite the conclusions of the meta-analysis."

For high-volume disease, he noted that there is growing consensus that triplet therapy is likely the best approach, but for low-volume disease, most physicians recommend a doublet of ADT plus an ARPI.

As for the meta-analysis finding that chemotherapy is a better choice than an ARPI for the first-line treatment of mCRPC, Dr Freedland observed: "The definitive trials of chemotherapy for mCRPC were more than 10 years ago, prior to the introduction of ARPIs." This makes it difficult to compare the therapies. "In practice, it is a moot point because no patient wants chemo." Consequently, first-line therapy for patients who have not received prior treatment for mCPRC is an ARPI, and a meta-analysis will not change this approach given the tolerability and side effect issues with chemotherapy, he said. "Also, ARPIs are very effective, so they are unlikely to be bumped from first-line."

Moreover, with ARPIs being used more and more prior to mCRPC, chemotherapy is likely to be used increasingly as first- or second-line mCRPC therapy, Dr Freedland added.

Studies that provide potentially useful information that can inform drug sequencing is not limited to RCTs or other large studies. For example, a small real-world study suggests that lutetium-177 PSMA-617 can be used following radium-223 for mCRPC with bone metastases. The agents emit different kinds of radiation (alpha particles and beta particles, respectively). The study included patients who received radium-223 for a median of 6 injections and subsequent lutetium-177-PSMA-617 for a median of 3.5 months. The median time between the treatments was 8 months. The median overall survival was 28 months from the start of radium-223 and 13.2 months from the start of lutetium-177 PSMA, Oliver Sartor, MD, of Tulane University School of Medicine in New Orleans, Louisiana reported in the Journal of Nuclear Medicine.5 The authors acknowledged that their small sample size precludes definitive conclusions, but noted that their data, especially related to the duration of lutetium-177-PSMA-617 therapy, suggest that the use of this medication after radium-223 is feasible in a real-world setting.

Trends May Lead to Greater Clarity

Some trends offer the promise of greater clarity about which drugs to use and when to use them. One is growing use of genomic and other biomarkers that can predict prostate cancer aggressiveness and response to therapy. Genetic testing, for example, can detect deleterious mutations in BCRA1/2 or other DNA-repair genes associated with high-risk prostate cancer, which could help decide on treatment. This would be the case with olaparib, a PARP inhibitor indicated for use in patients with certain genomic alterations, including BRCA-mutated mCRPC.

Another trend is growing use of PSMA PET in conjunction with computed tomography (PSMA PET/CT), which can identify metastases earlier and with greater accuracy compared with conventional imaging. The modality also can provide a better estimate of metastatic burden. Findings can help clinicians decide on the appropriateness and type of treatment, including metastasis-directed therapy. PSMA PET/CT already is used to select candidates for lutetium-177-PSMA-617.

Slow Uptake in Clinical Practice

Despite a growing array of pharmaceutical options for treating advanced prostate cancer, clinicians often do not follow guidelines regarding their use, according to real-world studies by Dr Freedland and colleagues. In a study of 14,780 men with mCRPC in the fee-for-service Medicare population, they found that 22% of them received no life-prolonging treatment such as ARPIs and chemotherapy after their mCRPC diagnosis, despite guidelines recommending such treatment.6 Guidelines recommend using ADT plus an ARPI as a standard of care for mHSPC, but in a study of 384 patients with de novo mHSPC in the Veterans Health Administration system, only 31% were prescribed this therapy, Dr Freedland and colleagues reported in a poster presentation at the 2024 ASCO Genitourinary Cancers Symposium.7 Another 42% of patients received ADT alone and 26% received first-generation nonsteroidal antiandrogens.

The slow uptake of novel treatments for advanced prostate cancer in clinical practice has not dampened enthusiasm for elucidating the optimal way to prescribe them. Whether through RCTs, retrospective analyses of real-world data, or meta-analyses, they continue to search for strategies that make the best use of these state-of-the-art therapies.

This article originally appeared on Renal and Urology News

Abiraterone By Austhera BioSciences For Hormone-Sensitive Prostate Cancer: Likelihood Of Approval

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Newly Diagnosed MHSPC: First-Line Treatment Options

Evan Y. Yu, MD, discusses how systemic therapy options for newly diagnosed metastatic hormone-sensitive prostate cancer include androgen deprivation therapy (ADT) combined with chemotherapy or androgen receptor pathway inhibitors (ARPIs) such as abiraterone or enzalutamide, with the choice of frontline treatment depending on factors such as disease burden and patient characteristics, while also considering the structural and physical differences between these ARPIs, which may influence their efficacy and adverse effect profiles.

Video content above is prompted by the following:

What systemic therapy options would you discuss with this patient?

Which do you consider for frontline treatment?

Thinking about the individual ARPI used in this setting, what are their similarities and differences in terms of structural formula and physical properties?

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