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Personalizing Prostate Cancer Treatment
Answering Key Clinical Questions in Personalizing Treatment for Patients With Metastatic Prostate Cancer

Released: July 26, 2023

Xin Gao
Xin Gao, MD
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Key Takeaways
  • Healthcare professionals should consider patients-specific characteristics (eg, disease volume, baseline comorbidities, fitness for chemotherapy) when deciding between doublet or triplet therapy for patients with mCSPC.
  • Recent FDA approvals of olaparib plus abiraterone and prednisone (or prednisolone) for BRCA-mutated mCRPC and talazoparib plus enzalutamide for homologous recombination repair gene‒mutated mCRPC expands treatment options for mCRPC.
  • A multidisciplinary approach to care ensures that patients understand the full scope of radium-223 and 177Lu-PSMA-617 treatments for their disease.

Treatment options for patients with prostate cancer have had significant advancements in recent years, with a focus on personalized approaches at each point in a patient’s disease. As treatment options continue to expand, we are able to tailor patients’ therapy based on disease characteristics, specific mutations, and patient preference to achieve improved outcomes.

In this commentary derived from a live symposium, I provide my thoughts on current clinical issues and nuances in the management of patients with prostate cancer. To listen to the replay of the live event, watch the on-demand video here.

What characteristics do you consider when deciding on the optimal treatment for patients with metastatic castration-sensitive prostate cancer (mCSPC)?
The vast majority of patients with mCSPC should receive either doublet therapy involving androgen-deprivation therapy (ADT) plus an AR pathway inhibitor (ARPI)—abiraterone, apalutamide, or enzalutamide—or triplet therapy involving ADT plus an ARPI—darolutamide or abiraterone—plus docetaxel. When deciding between ADT combinations as doublet or triplet therapies for patients with mCSPC, it is important to consider patients’ specific characteristics (eg, disease volume, baseline comorbidities, fitness for chemotherapy). One key factor to consider is disease volume, with high volume disease defined as visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis based on the eligibility criteria in the ARASENS and CHAARTED trials. People with high-volume disease should consider triplet therapy with ADT plus an ARPI and docetaxel. However, baseline comorbidities also should be considered because age and the patient’s overall frailty/fitness and general health affect medical decision-making, including the patient’s ability to tolerate chemotherapy.

For a younger patient with metastatic, high-volume disease—determined using the CHAARTED criteria—who is healthy otherwise, I recommend taking an aggressive treatment approach using triplet therapy based on data from the phase III ARASENS and PEACE-1 studies. The ARASENS study confirmed that the addition of darolutamide to ADT and docetaxel significantly improved overall survival. Similarly, the PEACE-1 study confirmed an overall survival benefit with the addition of abiraterone to ADT and docetaxel.

For most patients with low-volume, metachronous disease, however, I would favor doublet therapy with ADT plus ARPI.

What is the best treatment option for a patient experiencing disease progression after triplet therapy?
For patients experiencing disease progression on or after triplet therapy, I consider the same treatments I would for someone who received an ARPI and docetaxel sequentially. I strongly suggest molecular testing to look for targetable alterations in BRCA2, BRCA1, PALB2, and other homologous recombination defect genes for potential treatment with PARP inhibitors, as well as looking for microsatellite instability or mismatch repair deficiency for potential treatment with an immune checkpoint inhibitor.

One difference for patients who received triplet therapy is that there may be a longer disease-free interval between the completion of docetaxel therapy and progression compared with patients who received docetaxel as part of sequential therapy. For patients with disease progression after a longer treatment-free interval with docetaxel, it may be reasonable to consider rechallenging with chemotherapy. However, I would still recommend molecular testing to understand what the viable options are for the patient before deciding on chemotherapy rechallenge. Patients should also complete PSMA PET imaging to evaluate their candidacy for a PSMA-targeted radioligand therapy.

With the FDA approval of PARP inhibitors plus an ARPI for some patients with metastatic castration-resistant prostate cancer (mCRPC), how should we incorporate these options in clinical practice?
On May 31, 2023, the FDA approved the combination of olaparib plus abiraterone and prednisone (or prednisolone) for patients with deleterious or suspected deleterious BRCA-mutated mCRPC. Then, on June 20, 2023, the FDA approved the combination of talazoparib plus enzalutamide for homologous recombination repair gene‒mutated mCRPC. I have not yet had the opportunity to use either of these combinations in clinical practice, but these approvals do highlight the importance of molecular testing. I certainly will consider these combinations for my patients with mCRPC, but most patients will have likely received prior ARPI therapy in the CSPC setting, and it is unclear if continuing on an ARPI (or switching to another ARPI) and adding olaparib or talazoparib will result in better outcomes compared with a PARP inhibitor as a single agent.

There also are ongoing clinical trials evaluating PARP inhibitor combinations in mCSPC, so additional data may continue to change our clinical approaches in the future.

Should molecular testing be performed at progression after each line of therapy?
Molecular testing does not need to be performed at every disease progression. These tests are expensive and can result in a financial burden for patients. Furthermore, the likelihood of BRCA or homologous recombination repair gene status changing at each progression is low. In my clinical practice, I suggest molecular testing at the development of mCRPC and certainly when considering PARP inhibitor therapy or other targeted therapies as treatment options.

Finally, if patients experience further progression after using a PARP inhibitor in combination with an ARPI and they are chemotherapy naive, chemotherapy is a reasonable next treatment option. In addition to considering chemotherapy, patients also should complete PSMA PET imaging to evaluate their candidacy for a PSMA-targeted radioligand therapy.

In contrast to somatic testing, I do recommend germline testing for all patients with metastatic disease or high-risk at the time of diagnosis, as well as for those with a concerning family history.

When considering treatment with radium-223 or 177Lu- PSMA- 617, how do you talk to your patients about using a radiopharmaceutical?
Radium-223 has been a treatment option for patients with mCRPC for a long time, and now we have 177Lu-PSMA-617. 177Lu-PSMA-617 is approved by the FDA for the treatment of patients with PSMA-positive mCRPC who have been treated with an ARPI and taxane-based chemotherapy, and radium-223 is approved by the FDA for patients with mCRPC who have symptomatic bone metastases and no known visceral metastatic disease. When discussing these treatment options with patients at my institution, they hear from both medical oncology and our nuclear medicine group. The team discusses the difference between radium-223 and 177Lu-PSMA-617 with each patient. Radium-223 is an α-particle emitting radiotherapeutic that mimics calcium to form complexes with hydroxyapatite at areas of increased bone turnover, including in bone metastases. 177Lu-PSMA-617 is a PSMA-targeted radioligand therapy, which binds to PSMA on cell membranes and delivers the β-particle emitting radioactive atom, 177Lu, resulting in prostate cancer cell death.

While explaining the 2 components of targeted radioligand therapy—the targeting agent and the isotope—it is important to explain that the isotope selection and specificity of the targeting agent determine the toxicity profile associated with targeted radioligand therapy. For example, xerostomia (dry mouth) and dry eye adverse events are associated with PSMA expression on patients’ healthy salivary tissue and lacrimal glands.

Our nuclear medicine group also counsels patients on treatment logistics and precautions regarding radiation therapy. For example, they caution patients about care of bodily fluids post treatment and best practices for necessary precautions (eg, using their own toilet, closing the lid, and flushing twice if possible). Medical oncology leads the discussion on candidacy evaluation (including discussion of alternative treatment options), adverse event management, laboratory monitoring, and cancer symptom management.

Both medical oncology and the nuclear medicine group ensure that the patient’s lab results are adequate prior to treatment initiation. The clinical trial populations that were studied with these therapies had strict eligibility criteria, and it is incredibly important to quickly address any cytopenia or other laboratory issues that occur during treatment. I have been fairly cautious with patients who have baseline cytopenias, especially patients with a large burden of bone disease. There is potential for some patients to develop refractory cytopenias—5 adverse events that led to death in the VISION clinical trial were related to 177Lu-PSMA-617, including pancytopenias, bone marrow failure, and bleeding.

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