Carboplatin Shows Activity in HRR-Altered Metastatic Prostate Cancer

Platinum chemotherapy is not usually considered a standard targeted treatment for metastatic prostate cancer, but the phase 2 CIPHER trial suggests that carboplatin may have meaningful activity in men with mCRPC carrying homologous recombination repair (HRR) mutations. The study enrolled 39 patients with HRR-altered mCRPC who had already received at least one androgen-receptor pathway inhibitor and did not have access to PARP inhibitors. Carboplatin was given as a single agent every three weeks.

The main result was a PSA50 response in 41% of patients. Among 30 patients who could be assessed radiologically, 20% achieved a partial response and another 43.3% had stable disease. The median duration of response was 6.2 months. These are encouraging numbers for a relatively simple and inexpensive chemotherapy approach in a molecularly selected population. ASCO
The trial included several different HRR alterations. The most common were BRCA2 in 11 patients, ATM in 9, BRCA1 in 6, CDK12 in 3, with smaller numbers carrying RAD54L, BRIP1, PALB2, RAD51D, AKT1 or BARD1 alterations. This is important because HRR mutations do not all behave in the same way biologically, and prostate cancer responses to DNA-damaging therapies can vary substantially from one gene to another.

One of the most interesting findings was that patients with germline HRR mutations appeared more likely to respond than those with somatic-only alterations, with an odds ratio of 6.76 in multivariable analysis, although the result was borderline statistically significant and comes from a small study.

The biological rationale is straightforward. HRR-deficient tumour cells are less able to repair certain forms of DNA damage. Carboplatin creates DNA crosslinks that can become lethal when those repair systems are impaired. This overlaps conceptually with the rationale behind PARP inhibitors, although the two treatments act differently and should not be considered interchangeable.

The main caveat is the small, single-arm design. There was no control group, only 39 patients were treated, and the various HRR genes were represented by very small subgroups. The study therefore cannot tell us with confidence which individual mutations predict the strongest benefit. In particular, the presence of an ATM mutation should not automatically be assumed to confer the same platinum sensitivity seen with BRCA2, because ATM biology is different and responses to DNA-repair-targeted therapies are often less consistent.

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